Journal articles: 'Protein deposition disease'

1

Kaytor, Michael D., and Stephen T. Warren. "Aberrant Protein Deposition and Neurological Disease." Journal of Biological Chemistry 274, no. 53 (December 31, 1999): 37507–10. http://dx.doi.org/10.1074/jbc.274.53.37507.

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Leung, Nelson, Maria E. Drosou, and Samih H. Nasr. "Dysproteinemias and Glomerular Disease." Clinical Journal of the American Society of Nephrology 13, no. 1 (November 7, 2017): 128–39. http://dx.doi.org/10.2215/cjn.00560117.

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Dysproteinemia is characterized by the overproduction of an Ig by clonal expansion of cells from the B cell lineage. The resultant monoclonal protein can be composed of the entire Ig or its components. Monoclonal proteins are increasingly recognized as a contributor to kidney disease. They can cause injury in all areas of the kidney, including the glomerular, tubular, and vascular compartments. In the glomerulus, the major mechanism of injury is deposition. Examples of this include Ig amyloidosis, monoclonal Ig deposition disease, immunotactoid glomerulopathy, and cryoglobulinemic GN specifically from types 1 and 2 cryoglobulins. Mechanisms that do not involve Ig deposition include the activation of the complement system, which causes complement deposition in C3 glomerulopathy, and cytokines/growth factors as seen in thrombotic microangiopathy and precipitation, which is involved with cryoglobulinemia. It is important to recognize that nephrotoxic monoclonal proteins can be produced by clones from any of the B cell lineages and that a malignant state is not required for the development of kidney disease. The nephrotoxic clones that do not meet requirement for a malignant condition are now called monoclonal gammopathy of renal significance. Whether it is a malignancy or monoclonal gammopathy of renal significance, preservation of renal function requires substantial reduction of the monoclonal protein. With better understanding of the pathogenesis, clone-directed strategies, such as rituximab against CD20 expressing B cell and bortezomib against plasma cell clones, have been used in the treatment of these diseases. These clone-directed therapies been found to be more effective than immunosuppressive regimens used in nonmonoclonal protein–related kidney diseases.

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Haapasalo, Annakaisa, Jayashree Viswanathan, Lars Bertram, Hilkka Soininen, Rudolph E. Tanzi, and Mikko Hiltunen. "Emerging role of Alzheimer's disease-associated ubiquilin-1 in protein aggregation." Biochemical Society Transactions 38, no. 1 (January 19, 2010): 150–55. http://dx.doi.org/10.1042/bst0380150.

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Abnormal protein aggregation and intracellular or extracellular accumulation of misfolded and aggregated proteins are key events in the pathogenesis of different neurodegenerative diseases. Furthermore, endoplasmic reticulum stress and impairment of the ubiquitin–proteasome system probably contribute to neurodegeneration in these diseases. A characteristic feature of AD (Alzheimer's disease) is the abnormal accumulation of Aβ (amyloid β-peptide) in the brain. Evidence shows that the AD-associated PS (presenilin) also forms aggregates under certain conditions and that another AD-associated protein, ubiquilin-1, controls protein aggregation and deposition of aggregated proteins. Here, we review the current knowledge of ubiquilin-1 and PS in protein aggregation and related events that potentially influence neurodegeneration.

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Deret, S., J. Chomilier, D. B. Huang, J. L. Preud'homme, F. J. Stevens, and P. Aucouturier. "Molecular modeling of immunoglobulin light chains implicates hydrophobic residues in non-amyloid light chain deposition disease." Protein Engineering Design and Selection 10, no. 10 (October 1, 1997): 1191–97. http://dx.doi.org/10.1093/protein/10.10.1191.

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Samimi, Nastaran, Akiko Asada, and Kanae Ando. "Tau Abnormalities and Autophagic Defects in Neurodegenerative Disorders; A Feed-forward Cycle." Galen Medical Journal 9 (January 27, 2020): 1681. http://dx.doi.org/10.31661/gmj.v9i0.1681.

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Abnormal deposition of misfolded proteins is a neuropathological characteristic shared by many neurodegenerative disorders including Alzheimer’s disease (AD). Generation of excessive amounts of aggregated proteins and impairment of degradation systems for misfolded proteins such as autophagy can lead to accumulation of proteins in diseased neurons. Molecules that contribute to both these effects are emerging as critical players in disease pathogenesis. Furthermore, impairment of autophagy under disease conditions can be both a cause and a consequence of abnormal protein accumulation. Specifically, disease-causing proteins can impair autophagy, which further enhances the accumulation of abnormal proteins. In this short review, we focus on the relationship between the microtubule-associated protein tau and autophagy to highlight a feed-forward mechanism in disease pathogenesis. [GMJ.2020;9:e1681]

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Crestini, Alessio, Francesca Santilli, Stefano Martellucci, Elena Carbone, Maurizio Sorice, Paola Piscopo, and Vincenzo Mattei. "Prions and Neurodegenerative Diseases: A Focus on Alzheimer’s Disease." Journal of Alzheimer's Disease 85, no. 2 (January 18, 2022): 503–18. http://dx.doi.org/10.3233/jad-215171.

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Specific protein misfolding and aggregation are mechanisms underlying various neurodegenerative diseases such as prion disease and Alzheimer’s disease (AD). The misfolded proteins are involved in prions, amyloid-β (Aβ), tau, and α-synuclein disorders; they share common structural, biological, and biochemical characteristics, as well as similar mechanisms of aggregation and self-propagation. Pathological features of AD include the appearance of plaques consisting of deposition of protein Aβ and neurofibrillary tangles formed by the hyperphosphorylated tau protein. Although it is not clear how protein aggregation leads to AD, we are learning that the cellular prion protein (PrPC) plays an important role in the pathogenesis of AD. Herein, we first examined the pathogenesis of prion and AD with a focus on the contribution of PrPC to the development of AD. We analyzed the mechanisms that lead to the formation of a high affinity bond between Aβ oligomers (AβOs) and PrPC. Also, we studied the role of PrPC as an AβO receptor that initiates an AβO-induced signal cascade involving mGluR5, Fyn, Pyk2, and eEF2K linking Aβ and tau pathologies, resulting in the death of neurons in the central nervous system. Finally, we have described how the PrPC-AβOs interaction can be used as a new potential therapeutic target for the treatment of PrPC-dependent AD.

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Nalbantoglu, Josephine. "β-Amyloid Protein in Alzheimer's Disease." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 18, S3 (August 1991): 424–27. http://dx.doi.org/10.1017/s0317167100032595.

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ABSTRACT:β-amyloid protein, a 42-43 amino acid polypeptide, accumulates abnormally in senile plaques and the cerebral vasculature in Alzheimer's disease. This polypeptide is derived from a membrane-associated precursor which has several isoforms expressed in many tissues. The precursor protein is processed constitutively within the P-amyloid domain, leading to the release of the large β-terminal portion into the extracellular medium, β-amyloid protein may be toxic to certain neuronal cell types and its early deposition may be an important event in the pathogenesis of Alzheimer's disease.

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Boldueva, Svetlana A., Dmitriy S. Evdokimov, Natalia S. Shvets, Anahit V. Shahbazyan, Elena Yu Kalinina, and Lyubov B. Mitrofanova. "Systemic transtiretin amyloidosis in the elderly patient with recurrent pleural effusions." HERALD of North-Western State Medical University named after I.I. Mechnikov 13, no. 3 (October 15, 2021): 91–98. http://dx.doi.org/10.17816/mechnikov79512.

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Systemic amyloidosis is a group of diseases associated with extracellular deposition of fibrillar proteins, which leads to a loss of normal organ structure and function. Transthyretin amyloidosis occurs with the deposition of amyloid, consisting of transthyretin transport protein, and can be a genetic or degenerative disease of senility (acquired from the deposition of wild-type transthyretin). The article describes the clinical case of transthyretine amyloidosis in elderly patient, manifested by recurrent pleural effusions and biventricular heart failure demonstrating the complexity of timely diagnosis of wild-type transthyretin amyloidosis.

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Thorp, K. E., James A. Thorp, Elise M. Thorp, Margery M. Thorp, and Paul R. Walker. "COVID-19: Energy, Protein Folding & Prion Disease." Gazette of Medical Sciences 3, no. 1 (September 13, 2022): 179–206. http://dx.doi.org/10.46766/thegms.neuro.22083101.

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The recent recognition of intravascular amyloid formation with deposition of insoluble microthrombi throughout the circulatory system in primary COVID-19 infection or following administration of mRNA vaccines is a pivotal discovery that alters conventional notions about the nature of the underlying pathologic process at play in SARS-CoV-2 infection.

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Mold, Matthew John, Adam O’Farrell, Benjamin Morris, and Christopher Exley. "Aluminum and Neurofibrillary Tangle Co-Localization in Familial Alzheimer’s Disease and Related Neurological Disorders." Journal of Alzheimer's Disease 78, no. 1 (October 27, 2020): 139–49. http://dx.doi.org/10.3233/jad-200838.

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Background: Protein misfolding disorders are frequently implicated in neurodegenerative conditions. Familial Alzheimer’s disease (fAD) is an early-onset and aggressive form of Alzheimer’s disease (AD), driven through autosomal dominant mutations in genes encoding the amyloid precursor protein and presenilins 1 and 2. The incidence of epilepsy is higher in AD patients with shared neuropathological hallmarks in both disease states, including the formation of neurofibrillary tangles. Similarly, in Parkinson’s disease, dementia onset is known to follow neurofibrillary tangle deposition. Objective: Human exposure to aluminum has been linked to the etiology of neurodegenerative conditions and recent studies have demonstrated a high level of co-localization between amyloid-β and aluminum in fAD. In contrast, in a donor exposed to high levels of aluminum later developing late-onset epilepsy, aluminum and neurofibrillary tangles were found to deposit independently. Herein, we sought to identify aluminum and neurofibrillary tangles in fAD, Parkinson’s disease, and epilepsy donors. Methods: Aluminum-specific fluorescence microscopy was used to identify aluminum in neurofibrillary tangles in human brain tissue. Results: We observed aluminum and neurofibrillary-like tangles in identical cells in all respective disease states. Co-deposition varied across brain regions, with aluminum and neurofibrillary tangles depositing in different cellular locations of the same cell. Conclusion: Neurofibrillary tangle deposition closely follows cognitive-decline, and in epilepsy, tau phosphorylation associates with increased mossy fiber sprouting and seizure onset. Therefore, the presence of aluminum in these cells may exacerbate the accumulation and misfolding of amyloidogenic proteins including hyperphosphorylated tau in fAD, epilepsy, and Parkinson’s disease.

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Minnella, Angelo Maria, Roberta Rissotto, Elena Antoniazzi, Marco Di Girolamo, Marco Luigetti, Martina Maceroni, Daniela Bacherini, Benedetto Falsini, Stanislao Rizzo, and Laura Obici. "Ocular Involvement in Hereditary Amyloidosis." Genes 12, no. 7 (June 22, 2021): 955. http://dx.doi.org/10.3390/genes12070955.

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The term amyloidosis describes a group of rare diseases caused by protein conformation abnormalities resulting in extracellular deposition and accumulation of insoluble fibrillar aggregates. So far, 36 amyloid precursor proteins have been identified, and each one is responsible for a specific disease entity. Transthyretin amyloidosis (ATTRv) is one of the most common forms of systemic and ocular amyloidosis, due to the deposition of transthyretin (TTR), which is a transport protein mainly synthesized in the liver but also in the retinal pigment epithelial cells. ATTRv amyloidosis may be misdiagnosed with several other conditions, resulting in a significant diagnostic delay. Gelsolin and keratoepithelin are other proteins that, when mutated, are responsible for a systemic amyloid disease with significant ocular manifestations that not infrequently appear before systemic involvement. The main signs of ocular amyloid deposition are in the cornea, irido-corneal angle and vitreous, causing complications related to vasculopathy and neuropathy at the local level. This review aims at describing the main biochemical, histopathological and clinical features of systemic amyloidosis associated with eye involvement, with particular emphasis on the inherited forms. We discuss currently available treatments, focusing on ocular involvement and specific ophthalmologic management and highlighting the importance of a prompt treatment for the potential sight-threatening complications derived from amyloid deposition in ocular tissues.

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Honjo, Kie, Sandra E. Black, and Nicolaas P. L. G. Verhoeff. "Alzheimer's Disease, Cerebrovascular Disease, and the β-amyloid Cascade." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 39, no. 6 (November 2012): 712–28. http://dx.doi.org/10.1017/s0317167100015547.

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Alzheimer's disease (AD), considered the commonest neurodegenerative cause of dementia, is associated with hallmark pathologies including extracellular amyloid-β protein (Aβ) deposition in extracellular senile plaques and vessels, and intraneuronal tau deposition as neurofibrillary tangles. Although AD is usually categorized as neurodegeneration distinct from cerebrovascular disease (CVD), studies have shown strong links between AD and CVD. There is evidence that vascular risk factors and CVD may accelerate Aβ 40-42 production/ aggregation/deposition and contribute to the pathology and symptomatology of AD. Aβ deposited along vessels also causes cerebral amyloid angiopathy. Amyloid imaging allowsin vivodetection of AD pathology, opening the way for prevention and early treatment, if disease-modifying therapies in the pipeline show safety and efficacy. In this review, we review the role of vascular factors and Aβ, underlining that vascular risk factor management may be important for AD prevention and treatment.

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Selkoe, D., H. Mori, and C. Joachim. "EXTRACEREBRAL DEPOSITION OF β-AMYLOID PROTEIN (βAP) IN ALZHEIMERʼS DISEASE." Journal of Neuropathology and Experimental Neurology 49, no. 3 (May 1990): 309. http://dx.doi.org/10.1097/00005072-199005000-00150.

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A, Sandhya, and Gomathi Kannayiram. "ALZHEIMER’S DISEASE THERAPEUTIC APPROACHES." Asian Journal of Pharmaceutical and Clinical Research 11, no. 7 (July 7, 2018): 17. http://dx.doi.org/10.22159/ajpcr.2018.v11i7.25104.

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A protein is a large biomolecule which consists of one or more chains of amino acid residues. Proteins exhibit a biological phenomenon in which, they are misfolded as aggregates (i.e., accumulate and clump together) either intra- or extracellularly. This process plays a central role in the pathogenesis of Alzheimer’s disease (AD) and diabetes mellitus (DM) - 2 and common for many degenerative diseases. In this case, the histopathological consequences of protein misfolding such as sensile plaques and neurofibrillary tangles in AD and lewy bodies in Parkinson’s disease occur. 8–10% of adult population shares risk factors with AD. Amyloid fibrils which build up in tissue as an abnormal protein form Amyloidosis. Conformational change in three-dimensional structure forms amyloid fibrils. Type 2 DM is characterized by the deposition of islet amyloid polypeptide within beta cells of the pancreas which leads to chronic cerebral hypoperfusion that result in degeneration of neuroglial cells.

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Tsoi, Phoebe S., My Diem Quan, Josephine C. Ferreon, and Allan Chris M. Ferreon. "Aggregation of Disordered Proteins Associated with Neurodegeneration." International Journal of Molecular Sciences 24, no. 4 (February 8, 2023): 3380. http://dx.doi.org/10.3390/ijms24043380.

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Cellular deposition of protein aggregates, one of the hallmarks of neurodegeneration, disrupts cellular functions and leads to neuronal death. Mutations, posttranslational modifications, and truncations are common molecular underpinnings in the formation of aberrant protein conformations that seed aggregation. The major proteins involved in neurodegeneration include amyloid beta (Aβ) and tau in Alzheimer’s disease, α-synuclein in Parkinson’s disease, and TAR DNA-binding protein (TDP-43) in amyotrophic lateral sclerosis (ALS). These proteins are described as intrinsically disordered and possess enhanced ability to partition into biomolecular condensates. In this review, we discuss the role of protein misfolding and aggregation in neurodegenerative diseases, specifically highlighting implications of changes to the primary/secondary (mutations, posttranslational modifications, and truncations) and the quaternary/supramolecular (oligomerization and condensation) structural landscapes for the four aforementioned proteins. Understanding these aggregation mechanisms provides insights into neurodegenerative diseases and their common underlying molecular pathology.

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Hardy, J. "Expression of normal sequence pathogenic proteins for neurodegenerative disease contributes to disease risk: ‘permissive templating’ as a general mechanism underlying neurodegeneration." Biochemical Society Transactions 33, no. 4 (August 1, 2005): 578–81. http://dx.doi.org/10.1042/bst0330578.

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Loci underlying autosomal dominant forms of most neurodegenerative disease have been identified: prion mutations cause Gerstmann Straussler syndrome and hereditary Creutzfeldt–Jakob disease, tau mutations cause autosomal dominant frontal temporal dementia and α-synuclein mutations cause autosomal dominant Parkinson's disease. In these cases, the pathogenic mutation is in the protein that is deposited in the diseased tissue and the whole protein is deposited. In Alzheimer's disease, mutations in amyloid precursor protein or in the presenilins cause autosomal dominant disease. These are the substrate and proteases responsible for the production of the deposited peptide Aβ. Thus, in all the cases, the mutations lead to the disease by a mechanism that involves the deposition process. Furthermore, sporadic forms of all these diseases are predisposed by genetic variability at the same loci, implying that the quantity of the normal protein influences the risk of this form of disease. These results show that the amount of pathogenic protein expression is a key factor in determining disease initiation. Recent work on transgenic models of these diseases is consistent with the view that there are two stages of pathogenesis: a concentration-dependent formation of a pathogenic protein oligomer followed by aggregation on to this oligomeric template by a process that is less dependent on the concentration of the protein.

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Zhou, Bin, and Masanori Fukushima. "Clinical Utility of the Pathogenesis-Related Proteins in Alzheimer’s Disease." International Journal of Molecular Sciences 21, no. 22 (November 17, 2020): 8661. http://dx.doi.org/10.3390/ijms21228661.

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Research on the Aβ cascade and alternations of biomarkers in neuro-inflammation, synaptic dysfunction, and neuronal injury followed by Aβ have progressed. But the question is how to use the biomarkers. Here, we examine the evidence and pathogenic implications of protein interactions and the time order of alternation. After the deposition of Aβ, the change of tau, neurofilament light chain (NFL), and neurogranin (Ng) is the main alternation and connection to others. Neuro-inflammation, synaptic dysfunction, and neuronal injury function is exhibited prior to the structural and metabolic changes in the brain following Aβ deposition. The time order of such biomarkers compared to the tau protein is not clear. Despite the close relationship between biomarkers and plaque Aβ deposition, several factors favor one or the other. There is an interaction between some proteins that can predict the brain amyloid burden. The Aβ cascade hypothesis could be the pathway, but not all subjects suffer from Alzheimer’s disease (AD) within a long follow-up, even with very elevated Aβ. The interaction of biomarkers and the time order of change require further research to identify the right subjects and right molecular target for precision medicine therapies.

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Romine, Isabelle C., and R. Luke Wiseman. "Starting at the beginning: endoplasmic reticulum proteostasis and systemic amyloid disease." Biochemical Journal 477, no. 9 (May 15, 2020): 1721–32. http://dx.doi.org/10.1042/bcj20190312.

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Systemic amyloid diseases are characterized by the deposition of an amyloidogenic protein as toxic oligomers and amyloid fibrils on tissues distal from the site of protein synthesis. Traditionally, these diseases have been viewed as disorders of peripheral target tissues where aggregates are deposited, and toxicity is observed. However, recent evidence highlights an important role for endoplasmic reticulum (ER) proteostasis pathways within tissues synthesizing and secreting amyloidogenic proteins, such as the liver, in the pathogenesis of these disorders. Here, we describe the pathologic implications of ER proteostasis and its regulation on the toxic extracellular aggregation of amyloidogenic proteins implicated in systemic amyloid disease pathogenesis. Furthermore, we discuss the therapeutic potential for targeting ER proteostasis to reduce the secretion and toxic aggregation of amyloidogenic proteins to mitigate peripheral amyloid-associated toxicity involved in the onset and progression of systemic amyloid diseases.

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Jankovska, Nikol, Tomas Olejar, and Radoslav Matej. "Extracellular Amyloid Deposits in Alzheimer’s and Creutzfeldt–Jakob Disease: Similar Behavior of Different Proteins?" International Journal of Molecular Sciences 22, no. 1 (December 22, 2020): 7. http://dx.doi.org/10.3390/ijms22010007.

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Neurodegenerative diseases are characterized by the deposition of specific protein aggregates, both intracellularly and/or extracellularly, depending on the type of disease. The extracellular occurrence of tridimensional structures formed by amyloidogenic proteins defines Alzheimer’s disease, in which plaques are composed of amyloid β-protein, while in prionoses, the same term “amyloid” refers to the amyloid prion protein. In this review, we focused on providing a detailed didactic description and differentiation of diffuse, neuritic, and burnt-out plaques found in Alzheimer’s disease and kuru-like, florid, multicentric, and neuritic plaques in human transmissible spongiform encephalopathies, followed by a systematic classification of the morphological similarities and differences between the extracellular amyloid deposits in these disorders. Both conditions are accompanied by the extracellular deposits that share certain signs, including neuritic degeneration, suggesting a particular role for amyloid protein toxicity.

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Almadhoun, Osama F., Philip J. Katzman, and Thomas Rossi. "Collagenous Colitis Associated with Protein Losing Enteropathy in a Toddler." Case Reports in Gastrointestinal Medicine 2014 (2014): 1–4. http://dx.doi.org/10.1155/2014/209624.

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Collagenous mucosal inflammatory disease is a rare gastrointestinal disorder that involves the columnar lining of gastric and intestinal mucosa and is characterized by a distinct subepithelial collagen deposition. Recent clinical and pathological evidence have indicated that collagenous mucosal inflammatory disease can be extensive disease that may concomitantly involve several gastrointestinal sites at the same time. This entity, however, occurs infrequently in children. It is even less common to find concomitant depositions of collagen in the mucosa of gastrointestinal sites other than the colon. Only two cases in pediatric literature reported concomitant involvement, one with gastric and colonic involvement and the other one with gastroduodenocolitis. We are reporting a 15-month-old boy who presented with severe diarrhea and diffuse edema secondary to hypoalbuminemia. Further testing documented protein losing enteropathy (PLE) associated with collagenous colitis.

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Yu, Chiun-Chieh, Chia-Yin Lu, Meng-Hsiang Chen, Yueh-Sheng Chen, Cheng-Hsien Lu, Yi-Yun Lin, Kun-Hsien Chou, and Wei-Che Lin. "Brain Atrophy Mediates the Relationship between Misfolded Proteins Deposition and Cognitive Impairment in Parkinson’s Disease." Journal of Personalized Medicine 11, no. 8 (July 23, 2021): 702. http://dx.doi.org/10.3390/jpm11080702.

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Parkinson’s disease is associated with cognitive decline, misfolded protein deposition and brain atrophy. We herein hypothesized that structural abnormalities may be mediators between plasma misfolded proteins and cognitive functions. Neuropsychological assessments including five domains (attention, executive, speech and language, memory and visuospatial functions), ultra-sensitive immunomagnetic reduction-based immunoassay (IMR) measured misfolded protein levels (phosphorylated-Tau, Amyloidβ-42 and 40, α-synuclein and neurofilament light chain) and auto-segmented brain volumetry using FreeSurfur were performed for 54 Parkinson’s disease (PD) patients and 37 normal participants. Our results revealed that PD patients have higher plasma misfolded protein levels. Phosphorylated-Tau (p-Tau) and Amyloidβ-42 (Aβ-42) were correlated with atrophy of bilateral cerebellum, right caudate nucleus, and right accumbens area (RAA). In mediation analysis, RAA atrophy completely mediated the relationship between p-Tau and digit symbol coding (DSC). RAA and bilateral cerebellar cortex atrophy partially mediated the Aβ-42 and executive function (DSC and abstract thinking) relationship. Our study concluded that, in PD, p-Tau deposition adversely impacts DSC by causing RAA atrophy. Aβ-42 deposition adversely impacts executive functions by causing RAA and bilateral cerebellum atrophy.

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Hillis, Graham S., and Alison M. MacLeod. "Integrins and Disease." Clinical Science 91, no. 6 (December 1, 1996): 639–50. http://dx.doi.org/10.1042/cs0910639.

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1. Adhesion is a vital property of cells. It provides a stable environment for cell growth and differentiation and allows cells to migrate. 2. The interaction between cells and their extracellular matrices is also an important factor in the regulation of further protein deposition. Likewise, matrix proteins can influence cellular function thus creating a complex feedback mechanism. 3. The adherence of cells to each other, their extracellular matrices and endothelial surfaces is mediated by a variety of membrane proteins collectively known as adhesion molecules. 4. Adhesion molecules can be further divided into four subfamilies: the integrins, the selectins, the cadherins and the immunoglobulin superfamily. This article will review our current knowledge of the integrin family of adhesion receptors, focusing principally on their role in the pathogenesis of human disease.

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Mputhia, Zoe, Eugene Hone, Timir Tripathi, Tim Sargeant, Ralph Martins, and Prashant Bharadwaj. "Autophagy Modulation as a Treatment of Amyloid Diseases." Molecules 24, no. 18 (September 16, 2019): 3372. http://dx.doi.org/10.3390/molecules24183372.

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Amyloids are fibrous proteins aggregated into toxic forms that are implicated in several chronic disorders. More than 30 diseases show deposition of fibrous amyloid proteins associated with cell loss and degeneration in the affected tissues. Evidence demonstrates that amyloid diseases result from protein aggregation or impaired amyloid clearance, but the connection between amyloid accumulation and tissue degeneration is not clear. Common examples of amyloid diseases are Alzheimer’s disease (AD), Parkinson’s disease (PD) and tauopathies, which are the most common forms of neurodegenerative diseases, as well as polyglutamine disorders and certain peripheral metabolic diseases. In these diseases, increased accumulation of toxic amyloid proteins is suspected to be one of the main causative factors in the disease pathogenesis. It is therefore important to more clearly understand how these toxic amyloid proteins accumulate as this will aide in the development of more effective preventive and therapeutic strategies. Protein homeostasis, or proteostasis, is maintained by multiple cellular pathways—including protein synthesis, quality control, and clearance—which are collectively responsible for preventing protein misfolding or aggregation. Modulating protein degradation is a very complex but attractive treatment strategy used to remove amyloid and improve cell survival. This review will focus on autophagy, an important clearance pathway of amyloid proteins, and strategies for using it as a potential therapeutic target for amyloid diseases. The physiological role of autophagy in cells, pathways for its modulation, its connection with apoptosis, cell models and caveats in developing autophagy as a treatment and as a biomarker is discussed.

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KALARIA, RAJESH N. "Cerebrovascular Degeneration Is Related to Amyloid-? Protein Deposition in Alzheimer's Disease." Annals of the New York Academy of Sciences 826, no. 1 Cerebrovascul (September 1997): 263–71. http://dx.doi.org/10.1111/j.1749-6632.1997.tb48478.x.

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Demeule, Barthélemy, Robert Gurny, and Tudor Arvinte. "Where disease pathogenesis meets protein formulation: Renal deposition of immunoglobulin aggregates." European Journal of Pharmaceutics and Biopharmaceutics 62, no. 2 (February 2006): 121–30. http://dx.doi.org/10.1016/j.ejpb.2005.08.008.

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Wang, Wei, Xun-Hu Gu, Min Li, Zhi-Juan Cheng, Sheng Tian, Ying Liao, and Xu Liu. "MicroRNA-155-5p Targets SKP2, Activates IKKβ, Increases Aβ Aggregation, and Aggravates a Mouse Alzheimer Disease Model." Journal of Neuropathology & Experimental Neurology 81, no. 1 (December 3, 2021): 16–26. http://dx.doi.org/10.1093/jnen/nlab116.

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Abstract The nuclear factor kappa B (NF-κB) pathway and inhibitor of NF-κB kinase β (IKKβ) are involved in Alzheimer disease (AD) pathogenesis. This study explored the mechanisms underlying IKKβ-mediated Aβ aggregation and neuron regeneration in APP.PS1 mice. Adenoviral transduction particles were injected into the hippocampal CA1 region of the mice to knock down or inhibit target genes. Morris water maze was performed to evaluate the cognitive function of the mice. Aβ deposition was determined by histological examination. sh-IKKβ plasmids and microRNA (miR)-155-5p inhibitor were transfected into Aβ1-42-induced N2a cells. The expressions of AD-related proteins were detected by Western blot. The interaction between S-phase kinase-associated protein 2 (SKP2) and IKKβ was assessed by co-immunoprecipitation. IKKβ knockdown (KD) and miR-155-5p inhibition ameliorated cognitive impairment, improved neuron regeneration, and attenuated Aβ deposition in APP/PS1 mice. SKP2 KD aggravated cognitive impairment, inhibited neuron regeneration, and promoted Aβ deposition in the mice. SKP2 regulated the stability of IKKβ protein via ubiquitination. MiR-155-5p regulates Aβ deposition and the expression of Aβ generation-related proteins in N2a cells via targeting SKP2. These results indicate that the miR-155-5p/SKP2/IKKβ axis was critical for pathogenesis in this AD model and suggest the potential of miR-155-5p as a target for AD treatment.

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Hamano, Tadanori, Kouji Hayashi, Norimichi Shirafuji, and Yasunari Nakamoto. "The Implications of Autophagy in Alzheimer’s Disease." Current Alzheimer Research 15, no. 14 (November 2, 2018): 1283–96. http://dx.doi.org/10.2174/1567205015666181004143432.

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The pathogenic mechanisms of Alzheimer’s Disease (AD) involve the deposition of abnormally misfolded proteins, amyloid β protein (Aβ) and tau protein. Aβ comprises senile plaques, and tau aggregates form Neurofibrillary Tangles (NFTs), both of which are hallmarks of AD. Autophagy is the main conserved pathway for the degeneration of aggregated proteins, Aβ, tau and dysfunctional organelles in the cell. Many animal model studies have demonstrated that autophagy normally functions as the protective factor against AD progression associated with intracytoplasmic toxic Aβ and tau aggregates. The upregulation of autophagy can also be favorable in AD treatment. An improved understanding of the signaling pathways that regulate autophagy is critical to developing AD treatments. The cellular and molecular machineries of autophagy, their function in the pathogenesis of AD, and current drug discovery strategies will be discussed in this review.

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Ferrer, I., B. Puig, R. Blanco, and E. Martı́. "Prion protein deposition and abnormal synaptic protein expression in the cerebellum in Creutzfeldt–Jakob disease." Neuroscience 97, no. 4 (May 2000): 715–26. http://dx.doi.org/10.1016/s0306-4522(00)00045-2.

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Butterfield, JH, GM Kephart, PM Banks, and GJ Gleich. "Extracellular deposition of eosinophil granule major basic protein in lymph nodes of patients with Hodgkin's disease." Blood 68, no. 6 (December 1, 1986): 1250–56. http://dx.doi.org/10.1182/blood.v68.6.1250.1250.

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Abstract Lymph nodes from each of the four histologic types of Hodgkin's disease were examined for the presence of eosinophils and for eosinophil degranulation by immunofluorescent localization of eosinophil granule major basic protein (MBP). Eosinophil degranulation shown by MBP deposition outside of eosinophils was found in six of eight nodes from patients with nodular sclerosing disease and in two of eight nodes from patients with lymphocyte depletion-type disease. Three nodes of the mixed cellularity type, one node of the lymphocyte predominance type, and one lymph node of the lymphocyte depletion type showed one or two small foci of extracellular MBP deposition. Lymph nodes from patients without Hodgkin's disease showed no extracellular deposition of MBP. Large numbers of eosinophils were found in seven of eight nodes of the nodular sclerosing variant, but were less frequently seen among the other types of Hodgkin's disease. The presence of extracellular MBP in lymph nodes of patients with Hodgkin's disease indicates that eosinophil degranulation commonly occurs and suggests that the released eosinophil granule proteins may participate in the inflammatory reaction in this disorder more extensively than is presently appreciated.

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Butterfield, JH, GM Kephart, PM Banks, and GJ Gleich. "Extracellular deposition of eosinophil granule major basic protein in lymph nodes of patients with Hodgkin's disease." Blood 68, no. 6 (December 1, 1986): 1250–56. http://dx.doi.org/10.1182/blood.v68.6.1250.bloodjournal6861250.

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Lymph nodes from each of the four histologic types of Hodgkin's disease were examined for the presence of eosinophils and for eosinophil degranulation by immunofluorescent localization of eosinophil granule major basic protein (MBP). Eosinophil degranulation shown by MBP deposition outside of eosinophils was found in six of eight nodes from patients with nodular sclerosing disease and in two of eight nodes from patients with lymphocyte depletion-type disease. Three nodes of the mixed cellularity type, one node of the lymphocyte predominance type, and one lymph node of the lymphocyte depletion type showed one or two small foci of extracellular MBP deposition. Lymph nodes from patients without Hodgkin's disease showed no extracellular deposition of MBP. Large numbers of eosinophils were found in seven of eight nodes of the nodular sclerosing variant, but were less frequently seen among the other types of Hodgkin's disease. The presence of extracellular MBP in lymph nodes of patients with Hodgkin's disease indicates that eosinophil degranulation commonly occurs and suggests that the released eosinophil granule proteins may participate in the inflammatory reaction in this disorder more extensively than is presently appreciated.

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Dunlop, Rachael A., Roger T. Dean, and Kenneth J. Rodgers. "The impact of specific oxidized amino acids on protein turnover in J774 cells." Biochemical Journal 410, no. 1 (January 29, 2008): 131–40. http://dx.doi.org/10.1042/bj20070161.

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Oxidized protein deposition and accumulation have been implicated in the aetiology of a wide variety of age-related pathologies. Protein oxidation in vivo commonly results in the in situ modification of amino acid side chains, generating new oxidized amino acid residues in proteins. We have demonstrated previously that certain oxidized amino acids can be (mis)incorporated into cell proteins in vitro via protein synthesis. In the present study, we show that incorporation of o- and m-tyrosine resulted in increased protein catabolism, whereas dopa incorporation generated proteins that were inefficiently degraded by cells. Incorporation of higher levels of L-dopa into proteins resulted in an increase in the activity of lysosomal cathepsins, increased autofluorescence and the generation of high-molecular-mass SDS-stable complexes, indicative of protein aggregation. These effects were due to proteins containing incorporated L-dopa, since they were not seen with the stereoisomer D-dopa, which enters the cell and generates the same reactive species as L-dopa, but cannot be incorporated into proteins. The present study highlights how the nature of the oxidative modification to the protein can determine the efficiency of its removal from the cell by proteolysis. Protection against the generation of dopa and other species that promote resistance to proteolysis might prove to be critical in preventing toxicity from oxidative stress in pathologies associated with protein deposition, such as atherosclerosis, Alzheimer's disease and Parkinson's disease.

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Maltsev, A. V., N. V. Dovidchenko, V. K. Uteshev, V. V. Sokolik, O. M. Shtang, M. A. Yakushin, N. M. Sokolova, A. K. Surin, and O. V. Galzitskaya. "Intensive protein synthesis in neurons and phosphorylation of beta-amyloid precursor protein and tau-protein are triggering factors of neuronal amyloidosis and Alzheimer's disease." Biomeditsinskaya Khimiya 59, no. 2 (2013): 144–70. http://dx.doi.org/10.18097/pbmc20135902144.

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Recently the studies of Alzheimer’s disease have become particularly actual and have attracted scientists from all over the world to this problem as a result of dissemination of this dangerous disorder. The reason for such pathogenesis is not known, but the final image, for the first time obtained on microscopic brain sections from patients with this disease more than a hundred years ago, is well known to clinicists. This is the deposition of Ab amyloid in the brain tissue of senile plaques and fibrils. Many authors suppose that the deposition of beta-amyloid provokes secondary neuronal changes which are the reason of neuron death. Other authors associate the death of neurons with hyperphosphorylation of tau-proteins which form neurofibrillar coils inside nerve cells and lead to their death. For creation of methods of preclinical diagnostics and effective treatment of Alzheimer’s disease novel knowledge is required on the nature of triggering factors of sporadic isoforms of Alzheimer’s disease, on cause-effect relationships of phosphorylation of amyloid precursor protein with formation of pathogenic beta-amyloids, on the relationship with these factors of hyperphosphorylation of tau-protein and neuron death. In this review we analyze the papers describing the increasing of intensity of biosynthesis in neurons in normal conditions and under the stress, the possibility of development of energetic unbalanced neurons and activation of their protective systems. Phosphorylation and hyperphosphorylation of tau-proteins is also tightly connected with protective mechanisms of cells and with processes of evacuation of phosphates, adenosine mono-phosphates and pyrophosphates from the region of protein synthesis. Upon long and high intensity of protein synthesis the protective mechanisms are overloaded and the complementarity of metabolitic processes is disturbed. This results in dysfunction of neurons, transport collapse, and neuron death.

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Guan, Jian, Shikha Mishra, Rodney H. Falk, and Ronglih Liao. "Current perspectives on cardiac amyloidosis." American Journal of Physiology-Heart and Circulatory Physiology 302, no. 3 (February 2012): H544—H552. http://dx.doi.org/10.1152/ajpheart.00815.2011.

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Amyloidosis represents a group of diseases in which proteins undergo misfolding to form insoluble fibrils with subsequent tissue deposition. While almost all deposited amyloid fibers share a common nonbranched morphology, the affected end organs, clinical presentation, treatment strategies, and prognosis vary greatly among this group of diseases and are largely dependent on the specific amyloid precursor protein. To date, at least 27 precursor proteins have been identified to result in either local tissue or systemic amyloidosis, with nine of them manifesting in cardiac deposition and resulting in a syndrome termed “cardiac amyloidosis” or “amyloid cardiomyopathy.” Although cardiac amyloidosis has been traditionally considered to be a rare disorder, as clinical appreciation and understanding continues to grow, so too has the prevalence, suggesting that this disease may be greatly underdiagnosed. The most common form of cardiac amyloidosis is associated with circulating amyloidogenic monoclonal immunoglobulin light chain proteins. Other major cardiac amyloidoses result from a misfolding of products of mutated or wild-type transthyretin protein. While the various cardiac amyloidoses share a common functional consequence, namely, an infiltrative cardiomyopathy with restrictive pathophysiology leading to progressive heart failure, the underlying pathophysiology and clinical syndrome varies with each precursor protein. Herein, we aim to provide an up-to-date overview of cardiac amyloidosis from nomenclature to molecular mechanisms and treatment options, with a particular focus on amyloidogenic immunoglobulin light chain protein cardiac amyloidosis.

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Emond-Boisjoly, Marie-Eve, Emilie Lemieux-Blanchard, Antonia Maietta, and Stéphanie Forté. "Multiple Myeloma Presenting as Acute Kidney Failure Secondary to Lambda Light Chain Deposition." Journal of Hematology Research 9 (November 30, 2022): 10–14. http://dx.doi.org/10.12974/2312-5411.2022.09.03.

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Renal monoclonal immunoglobulin deposition disease (MIDD) is a rare disease defined by deposition of monoclonal light chains and/or heavy chains on basement membranes and vascular walls of the kidney. We describe a case of a 71-year-old woman with kidney failure secondary to monoclonal immunoglobulin deposition disease lambda in association with plasma cell dyscrasia. Her initial serum protein electrophoresis did not demonstrate a monoclonal protein, and classic cast nephropathy was absent on renal biopsy. However, lambda light chain deposits and associated changes confirmed MIDD. She achieved a very good partial response (VGRP) after 8 cycles of CyBorD (cyclophosphamide, bortezomib, dexamethasone) and her kidney function improved. This case highlights the importance of an early diagnostic with renal biopsy to prevent end-stage renal disease. A review of the existing literature and a discussion on the management of the disease is presented.

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Florczuk-Kołomyja, Patrycja, Paweł Kołomyja, Wiesław Świderek, and Joanna Gruszczyńska. "Amyloidogenic proteins and occurrence of different amyloidosis in different animal species." Acta Scientiarum Polonorum Zootechnica 19, no. 3 (March 12, 2021): 3–14. http://dx.doi.org/10.21005/asp.2020.19.3.01.

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Amyloidosis is a poly-systemic disease caused by extracellular deposition of biologically inactive amyloid proteins, most often in kidneys, liver, nervous system, thyroid, spleen and heart. Depending on the site of production and deposition they can be classified into causing localised (organ-limited) and systemic amyloidosis. Disturbances in functioning of individual organs occur with an increase of the amount of accumulated protein what in turn may lead to the death of the affected individual. The occurrence of amyloidosis has been reported in human, but in animals, the most common form is AA amyloidosis, while AL amyloidosis is the least common. Due to the fact that symptoms of amyloidosis vary and often resemble those occurring in the course of other diseases, it is difficult to diagnose. Treatment of amyloidosis is aimed at improving functioning of the affected organs, yet the disease is incurable.

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Joachim, Catharine L., Hiroshi Mori, and Dennis J. Selkoe. "Amyloid β-protein deposition in tissues other than brain in Alzheimer's disease." Nature 341, no. 6239 (September 1989): 226–30. http://dx.doi.org/10.1038/341226a0.

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Cairns, N. J., A. Chadwick, P. J. Luthert, and P. L. Lantos. "Astrocytosis, βA4-protein deposition and paired helical filament formation in Alzheimer's disease." Journal of the Neurological Sciences 112, no. 1-2 (October 1992): 68–75. http://dx.doi.org/10.1016/0022-510x(92)90134-7.

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Mead, Simon, Jonathan D. F. Wadsworth, Marie-Claire Porter, Jacqueline M. Linehan, Wojciech Pietkiewicz, Graham S. Jackson, Sebastian Brandner, and John Collinge. "Variant Creutzfeldt-Jakob Disease With Extremely Low Lymphoreticular Deposition of Prion Protein." JAMA Neurology 71, no. 3 (March 1, 2014): 340. http://dx.doi.org/10.1001/jamaneurol.2013.5378.

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González-Sanmiguel, Juliana, Christina M. A. P. Schuh, Carola Muñoz-Montesino, Pamina Contreras-Kallens, Luis G. Aguayo, and Sebastian Aguayo. "Complex Interaction between Resident Microbiota and Misfolded Proteins: Role in Neuroinflammation and Neurodegeneration." Cells 9, no. 11 (November 13, 2020): 2476. http://dx.doi.org/10.3390/cells9112476.

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Neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and Creutzfeldt–Jakob disease (CJD) are brain conditions affecting millions of people worldwide. These diseases are associated with the presence of amyloid-β (Aβ), alpha synuclein (α-Syn) and prion protein (PrP) depositions in the brain, respectively, which lead to synaptic disconnection and subsequent progressive neuronal death. Although considerable progress has been made in elucidating the pathogenesis of these diseases, the specific mechanisms of their origins remain largely unknown. A body of research suggests a potential association between host microbiota, neuroinflammation and dementia, either directly due to bacterial brain invasion because of barrier leakage and production of toxins and inflammation, or indirectly by modulating the immune response. In the present review, we focus on the emerging topics of neuroinflammation and the association between components of the human microbiota and the deposition of Aβ, α-Syn and PrP in the brain. Special focus is given to gut and oral bacteria and biofilms and to the potential mechanisms associating microbiome dysbiosis and toxin production with neurodegeneration. The roles of neuroinflammation, protein misfolding and cellular mediators in membrane damage and increased permeability are also discussed.

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Malik, Talat H., Daniel P. Gitterman, Deborah P. Lavin, Hannah J. Lomax-Browne, E. Christina Hiemeyer, Linda B. Moran, Katharina Boroviak, et al. "Gain-of-function factor H–related 5 protein impairs glomerular complement regulation resulting in kidney damage." Proceedings of the National Academy of Sciences 118, no. 13 (March 22, 2021): e2022722118. http://dx.doi.org/10.1073/pnas.2022722118.

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Genetic variation within the factor H–related (FHR) genes is associated with the complement-mediated kidney disease, C3 glomerulopathy (C3G). There is no definitive treatment for C3G, and a significant proportion of patients develop end-stage renal disease. The prototypical example is CFHR5 nephropathy, through which an internal duplication within a single CFHR5 gene generates a mutant FHR5 protein (FHR5mut) that leads to accumulation of complement C3 within glomeruli. To elucidate how abnormal FHR proteins cause C3G, we modeled CFHR5 nephropathy in mice. Animals lacking the murine factor H (FH) and FHR proteins, but coexpressing human FH and FHR5mut (hFH-FHR5mut), developed glomerular C3 deposition, whereas mice coexpressing human FH with the normal FHR5 protein (hFH-FHR5) did not. Like in patients, the FHR5mut had a dominant gain-of-function effect, and when administered in hFH-FHR5 mice, it triggered C3 deposition. Importantly, adeno-associated virus vector-delivered homodimeric mini-FH, a molecule with superior surface C3 binding compared to FH, reduced glomerular C3 deposition in the presence of the FHR5mut. Our data demonstrate that FHR5mut causes C3G by disrupting the homeostatic regulation of complement within the kidney and is directly pathogenic in C3G. These results support the use of FH-derived molecules with enhanced C3 binding for treating C3G associated with abnormal FHR proteins. They also suggest that targeting FHR5 represents a way to treat complement-mediated kidney injury.

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Merlini, Giampaolo, and Marvin J. Stone. "Dangerous small B-cell clones." Blood 108, no. 8 (October 15, 2006): 2520–30. http://dx.doi.org/10.1182/blood-2006-03-001164.

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AbstractThe detection of a monoclonal immunoglobulin in serum or urine usually raises concerns about the size of the underlying B-cell-derived clone and possible systemic effects caused by its expansion. However, a small clone can synthesize a very toxic protein, producing devastating systemic damage and protean clinical presentations. The resulting “monoclonal component-related diseases,” although difficult to diagnose, may be progressive and even fatal. The monoclonal protein can aggregate and deposit systemically as occurs in light-chain amyloidosis, monoclonal immunoglobulin deposition disease, crystal-storing histiocytosis, and monoclonal cryoglobulinemia. Alternatively, some monoclonal proteins possess antibody activity toward autogenous antigens and cause chronic cold agglutinin disease, mixed cryoglobulinemia, and peripheral neuropathies. Other humoral mediators may contribute to neuropathy in variant disorders such as the POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) syndrome. The clone synthesizing the noxious monoclonal proteins is often small, and sensitive techniques may be required to detect these immunoglobulins. A delay in diagnosis can allow irreversible organ damage and dramatically shorten survival. Prompt recognition of suggestive signs and symptoms should trigger a thorough diagnostic approach to reach the correct diagnosis quickly, because this is the key to effective therapy. Although the treatment of these conditions is not optimal, significant advances have been made, improving the duration and quality of life.

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Bruno, Rosalia, Laura Pirisinu, Geraldina Riccardi, Claudia D’Agostino, Elena De Cecco, Giuseppe Legname, Franco Cardone, et al. "Gerstmann–Sträussler–Scheinker Disease with F198S Mutation Induces Independent Tau and Prion Protein Pathologies in Bank Voles." Biomolecules 12, no. 10 (October 21, 2022): 1537. http://dx.doi.org/10.3390/biom12101537.

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Gerstmann–Sträussler–Scheinker disease (GSS) is a rare genetic prion disease. A large GSS kindred linked to the serine-for-phenylalanine substitution at codon 198 of the prion protein gene (GSS-F198S) is characterized by conspicuous accumulation of prion protein (PrP)-amyloid deposits and neurofibrillary tangles. Recently, we demonstrated the transmissibility of GSS-F198S prions to bank vole carrying isoleucine at 109 PrP codon (BvI). Here we investigated: (i) the transmissibility of GSS-F198S prions to voles carrying methionine at codon 109 (BvM); (ii) the induction of hyperphosphorylated Tau (pTau) in two vole lines, and (iii) compared the phenotype of GSS-F198S-induced pTau with pTau induced in BvM following intracerebral inoculation of a familial Alzheimer’s disease case carrying Presenilin 1 mutation (fAD-PS1). We did not detect prion transmission to BvM, despite the high susceptibility of BvI previously observed. Immunohistochemistry established the presence of induced pTau depositions in vole brains that were not affected by prions. Furthermore, the phenotype of pTau deposits in vole brains was similar in GSS-F198S and fAD-PS1. Overall, results suggest that, regardless of the cause of pTau deposition and its relationship with PrPSc in GSS-F198S human-affected brains, the two components possess their own seeding properties, and that pTau deposition is similarly induced by GSS-F198S and fAD-PS1.

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Godoy, Maria Dantas Costa Lima, Marco Aurélio Fornazieri, Richard L. Doty, Fábio de Rezende Pinna, José Marcelo Farfel, Glaucia Bento dos Santos, Mariana Molina, et al. "Is Olfactory Epithelium Biopsy Useful for Confirming Alzheimer’s Disease?" Annals of Otology, Rhinology & Laryngology 128, no. 3 (December 2, 2018): 184–92. http://dx.doi.org/10.1177/0003489418814865.

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Objectives: The clinical symptoms of Alzheimer’s disease (AD) are preceded by a long asymptomatic period associated with “silent” deposition of aberrant paired helical filament (PHF)-tau and amyloid-beta proteins in brain tissue. Similar depositions have been reported within the olfactory epithelium (OE), a tissue that can be biopsied in vivo. The degree to which such biopsies are useful in identifying AD is controversial. This postmortem study had 3 main goals: first, to quantify the relative densities of AD-related proteins in 3 regions of the olfactory neuroepithelium, namely, the nasal septum, middle turbinate, and superior turbinate; second, to establish whether such densities are correlated among these epithelial regions as well as with semi-quantitative ratings of general brain cortex pathology; and third, to evaluate correlations between the protein densities and measures of antemortem cognitive function. Methods: Postmortem blocks of olfactory mucosa were obtained from 12 AD cadavers and 24 controls and subjected to amyloid-beta and PHF-tau immunohistochemistry. Results: We observed marked heterogeneity in the presence of the biomarkers of tau and amyloid-beta among the targeted olfactory epithelial regions. No significant difference was observed between the cadavers with AD and the controls regarding the concentration of these proteins in any of these epithelial regions. Only one correlation significant was evident, namely, that between the tau protein densities of the middle and the upper turbinate ( r = .58, P = .002). Conclusion: AD-related biomarker heterogeneity, which has not been previously demonstrated, makes comparisons across studies difficult and throws into question the usefulness of OE amyloid-beta and PHF-tau biopsies in detecting AD.

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Liberski, Pawel P., Don C. Guiroy, Elizabeth S. Williams, Anna Walis, and Herbert Budka. "Deposition patterns of disease-associated prion protein in captive mule deer brains with chronic wasting disease." Acta Neuropathologica 102, no. 5 (November 2001): 496–500. http://dx.doi.org/10.1007/s004010100417.

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Pluta, Ryszard, Marzena Ułamek-Kozioł, Sławomir Januszewski, and Stanisław J. Czuczwar. "Shared Genomic and Proteomic Contribution of Amyloid and Tau Protein Characteristic of Alzheimer’s Disease to Brain Ischemia." International Journal of Molecular Sciences 21, no. 9 (April 30, 2020): 3186. http://dx.doi.org/10.3390/ijms21093186.

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Post-ischemic brain damage is associated with the deposition of folding proteins such as the amyloid and tau protein in the intra- and extracellular spaces of brain tissue. In this review, we summarize the protein changes associated with Alzheimer’s disease and their gene expression (amyloid protein precursor and tau protein) after ischemia-reperfusion brain injury and their role in the post-ischemic injury. Recent advances in understanding the post-ischemic neuropathology have revealed dysregulation of amyloid protein precursor, α-secretase, β-secretase, presenilin 1 and 2, and tau protein genes after ischemic brain injury. However, reduced expression of the α-secretase in post-ischemic brain causes neurons to be less resistant to injury. In this review, we present the latest evidence that proteins associated with Alzheimer’s disease and their genes play a key role in progressive brain damage due to ischemia and reperfusion, and that an ischemic episode is an essential and leading supplier of proteins and genes associated with Alzheimer’s disease in post-ischemic brain. Understanding the underlying processes of linking Alzheimer’s disease-related proteins and their genes in post-ischemic brain injury with the risk of developing Alzheimer’s disease will provide the most significant goals for therapeutic development to date.

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Su, Chi-Ting, and Zsolt Urban. "LTBP4 in Health and Disease." Genes 12, no. 6 (May 23, 2021): 795. http://dx.doi.org/10.3390/genes12060795.

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Latent transforming growth factor β (TGFβ)-binding protein (LTBP) 4, a member of the LTBP family, shows structural homology with fibrillins. Both these protein types are characterized by calcium-binding epidermal growth factor-like repeats interspersed with 8-cysteine domains. Based on its domain composition and distribution, LTBP4 is thought to adopt an extended structure, facilitating the linear deposition of tropoelastin onto microfibrils. In humans, mutations in LTBP4 result in autosomal recessive cutis laxa type 1C, characterized by redundant skin, pulmonary emphysema, and valvular heart disease. LTBP4 is an essential regulator of TGFβ signaling and is related to development, immunity, injury repair, and diseases, playing a central role in regulating inflammation, fibrosis, and cancer progression. In this review, we focus on medical disorders or diseases that may be manipulated by LTBP4 in order to enhance the understanding of this protein.

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Cowan, Catherine M., David Shepherd, and Amritpal Mudher. "Insights from Drosophila models of Alzheimer's disease." Biochemical Society Transactions 38, no. 4 (July 26, 2010): 988–92. http://dx.doi.org/10.1042/bst0380988.

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AD (Alzheimer's disease) is a neurodegenerative disorder characterized by the abnormal hyperphosphorylation and aggregation of the microtubule-associated protein tau and the misfolding and deposition of Aβ peptide. The mechanisms by which tau and Aβ become abnormal is not clearly understood, neither is it known what role either protein plays in the neurodegenerative process underlying AD. We have modelled aspects of AD in Drosophila melanogaster to shed light on these processes and to further our understanding of the relationship between tau and amyloid in this disease.

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Kochumon, Sheena, Dhanya Yesodharan, KP Vinayan, Natasha Radhakrishnan, Jayesh Sheth, and Sheela Nampoothiri. "GM2 activator protein deficiency, mimic of Tay-Sachs disease." International Journal of Epilepsy 04, no. 02 (December 2017): 184–87. http://dx.doi.org/10.1016/j.ijep.2017.08.001.

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AbstractGM2 Gangliosidoses are a group of autosomal recessive genetic disorders caused by intra-lysosomal deposition of ganglioside GM2 mainly in the neuronal cells. GM2-Activator protein deficiency is an extremely rare type of GM2 gangliosidosis (AB variant) caused by the mutation of GM2A.We report a case of a female child who presented with clinical features similar to classical Tay-Sachs disease, but with normal beta hexosaminidase enzyme levels. Molecular study revealed a novel homozygous intronic mutation which confirmed the diagnosis of GM2 Activator protein deficiency. GM2 Activator protein deficiency is a mimic of Classical Tay-Sachs disease and should be a differential diagnosis in children who present with neuroregression, cherry red spots without hepatosplenomegaly and with normal beta hexosaminidase enzyme levels.

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Matlahov, Irina, and Patrick CA van der Wel. "Conformational studies of pathogenic expanded polyglutamine protein deposits from Huntington’s disease." Experimental Biology and Medicine 244, no. 17 (June 15, 2019): 1584–95. http://dx.doi.org/10.1177/1535370219856620.

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Huntington’s disease, like other neurodegenerative diseases, continues to lack an effective cure. Current treatments that address early symptoms ultimately fail Huntington’s disease patients and their families, with the disease typically being fatal within 10–15 years from onset. Huntington’s disease is an inherited disorder with motor and mental impairment, and is associated with the genetic expansion of a CAG codon repeat encoding a polyglutamine-segment-containing protein called huntingtin. These Huntington’s disease mutations cause misfolding and aggregation of fragments of the mutant huntingtin protein, thereby likely contributing to disease toxicity through a combination of gain-of-toxic-function for the misfolded aggregates and a loss of function from sequestration of huntingtin and other proteins. As with other amyloid diseases, the mutant protein forms non-native fibrillar structures, which in Huntington’s disease are found within patients’ neurons. The intracellular deposits are associated with dysregulation of vital processes, and inter-neuronal transport of aggregates may contribute to disease progression. However, a molecular understanding of these aggregates and their detrimental effects has been frustrated by insufficient structural data on the misfolded protein state. In this review, we examine recent developments in the structural biology of polyglutamine-expanded huntingtin fragments, and especially the contributions enabled by advances in solid-state nuclear magnetic resonance spectroscopy. We summarize and discuss our current structural understanding of the huntingtin deposits and how this information furthers our understanding of the misfolding mechanism and disease toxicity mechanisms. Impact statement Many incurable neurodegenerative disorders are associated with, and potentially caused by, the amyloidogenic misfolding and aggregation of proteins. Usually, complex genetic and behavioral factors dictate disease risk and age of onset. Due to its principally mono-genic origin, which strongly predicts the age-of-onset by the extent of CAG repeat expansion, Huntington’s disease (HD) presents a unique opportunity to dissect the underlying disease-causing processes in molecular detail. Yet, until recently, the mutant huntingtin protein with its expanded polyglutamine domain has resisted structural study at the atomic level. We present here a review of recent developments in HD structural biology, facilitated by breakthrough data from solid-state NMR spectroscopy, electron microscopy, and complementary methods. The misfolded structures of the fibrillar proteins inform our mechanistic understanding of the disease-causing molecular processes in HD, other CAG repeat expansion disorders, and, more generally, protein deposition disease.

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Magi, Simona, Pasqualina Castaldo, Maria Loredana Macrì, Marta Maiolino, Alessandra Matteucci, Guendalina Bastioli, Santo Gratteri, Salvatore Amoroso, and Vincenzo Lariccia. "Intracellular Calcium Dysregulation: Implications for Alzheimer’s Disease." BioMed Research International 2016 (2016): 1–14. http://dx.doi.org/10.1155/2016/6701324.

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Alzheimer’s Disease (AD) is a neurodegenerative disorder characterized by progressive neuronal loss. AD is associated with aberrant processing of the amyloid precursor protein, which leads to the deposition of amyloid-βplaques within the brain. Together with plaques deposition, the hyperphosphorylation of the microtubules associated protein tau and the formation of intraneuronal neurofibrillary tangles are a typical neuropathological feature in AD brains. Cellular dysfunctions involving specific subcellular compartments, such as mitochondria and endoplasmic reticulum (ER), are emerging as crucial players in the pathogenesis of AD, as well as increased oxidative stress and dysregulation of calcium homeostasis. Specifically, dysregulation of intracellular calcium homeostasis has been suggested as a common proximal cause of neural dysfunction in AD. Aberrant calcium signaling has been considered a phenomenon mainly related to the dysfunction of intracellular calcium stores, which can occur in both neuronal and nonneuronal cells. This review reports the most recent findings on cellular mechanisms involved in the pathogenesis of AD, with main focus on the control of calcium homeostasis at both cytosolic and mitochondrial level.

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Journal articles on the topic 'Protein deposition disease'

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