Zeitschriftenartikel: „Proteinopathy“

1

Taylor, J. Paul. „Multisystem proteinopathy: Table“. Neurology 85, Nr. 8 (24.07.2015): 658–60. http://dx.doi.org/10.1212/wnl.0000000000001862.

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2

Valderhaug, Vibeke D., Kristine Heiney, Ola Huse Ramstad, Geir Bråthen, Wei-Li Kuan, Stefano Nichele, Axel Sandvig und Ioanna Sandvig. „Early functional changes associated with alpha-synuclein proteinopathy in engineered human neural networks“. American Journal of Physiology-Cell Physiology 320, Nr. 6 (01.06.2021): C1141—C1152. http://dx.doi.org/10.1152/ajpcell.00413.2020.

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A patterned spread of proteinopathy represents a common characteristic of many neurodegenerative diseases. In Parkinson’s disease (PD), misfolded forms of α-synuclein proteins accumulate in hallmark pathological inclusions termed Lewy bodies and Lewy neurites. Such protein aggregates seem to affect selectively vulnerable neuronal populations in the substantia nigra and to propagate within interconnected neuronal networks. Research findings suggest that these proteinopathic inclusions are present at very early time points in disease development, even before clear behavioral symptoms of dysfunction arise. In this study, we investigate the early pathophysiology developing after induced formation of such PD-related α-synuclein inclusions in a physiologically relevant in vitro setup using engineered human neural networks. We monitor the neural network activity using multielectrode arrays (MEAs) for a period of 3 wk following proteinopathy induction to identify associated changes in network function, with a special emphasis on the measure of network criticality. Self-organized criticality represents the critical point between resilience against perturbation and adaptational flexibility, which appears to be a functional trait in self-organizing neural networks, both in vitro and in vivo. We show that although developing pathology at early onset is not clearly manifest in standard measurements of network function, it may be discerned by investigating differences in network criticality states.

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3

Paraskevas, George P., Mara Bourbouli, Ioannis Zaganas und Elisabeth Kapaki. „The emerging TDP-43 proteinopathy“. Neuroimmunology and Neuroinflammation 5, Nr. 5 (10.05.2018): 17. http://dx.doi.org/10.20517/2347-8659.2018.18.

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4

Bhuiyan, Md Shenuarin, J. Scott Pattison, Hanna Osinska, Jeanne James, James Gulick, Patrick M. McLendon, Joseph A. Hill, Junichi Sadoshima und Jeffrey Robbins. „Enhanced autophagy ameliorates cardiac proteinopathy“. Journal of Clinical Investigation 123, Nr. 12 (01.11.2013): 5284–97. http://dx.doi.org/10.1172/jci70877.

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5

Taylor, Laura M., Pamela J. McMillan, Brian C. Kraemer und Nicole F. Liachko. „Tau tubulin kinases in proteinopathy“. FEBS Journal 286, Nr. 13 (22.05.2019): 2434–46. http://dx.doi.org/10.1111/febs.14866.

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6

Chen, Han-Jou, und Jacqueline C. Mitchell. „Mechanisms of TDP-43 Proteinopathy Onset and Propagation“. International Journal of Molecular Sciences 22, Nr. 11 (02.06.2021): 6004. http://dx.doi.org/10.3390/ijms22116004.

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TDP-43 is an RNA-binding protein that has been robustly linked to the pathogenesis of a number of neurodegenerative disorders, including amyotrophic lateral sclerosis and frontotemporal dementia. While mutations in the TARDBP gene that codes for the protein have been identified as causing disease in a small subset of patients, TDP-43 proteinopathy is present in the majority of cases regardless of mutation status. This raises key questions regarding the mechanisms by which TDP-43 proteinopathy arises and spreads throughout the central nervous system. Numerous studies have explored the role of a variety of cellular functions on the disease process, and nucleocytoplasmic transport, protein homeostasis, RNA interactions and cellular stress have all risen to the forefront as possible contributors to the initiation of TDP-43 pathogenesis. There is also a small but growing body of evidence suggesting that aggregation-prone TDP-43 can recruit physiological TDP-43, and be transmitted intercellularly, providing a mechanism whereby small-scale proteinopathy spreads from cell to cell, reflecting the spread of clinical symptoms observed in patients. This review will discuss the potential role of the aforementioned cellular functions in TDP-43 pathogenesis, and explore how aberrant pathology may spread, and result in a feed-forward cascade effect, leading to robust TDP-43 proteinopathy and disease.

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Deng, Jianwen, Peng Wang, Xiaoping Chen, Haipeng Cheng, Jianghong Liu, Kazuo Fushimi, Li Zhu und Jane Y. Wu. „FUS interacts with ATP synthase beta subunit and induces mitochondrial unfolded protein response in cellular and animal models“. Proceedings of the National Academy of Sciences 115, Nr. 41 (24.09.2018): E9678—E9686. http://dx.doi.org/10.1073/pnas.1806655115.

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FUS (fused in sarcoma) proteinopathy is a group of neurodegenerative diseases characterized by the formation of inclusion bodies containing the FUS protein, including frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Previous studies show that mitochondrial damage is an important aspect of FUS proteinopathy. However, the molecular mechanisms by which FUS induces mitochondrial damage remain to be elucidated. Our biochemical and genetic experiments demonstrate that FUS interacts with the catalytic subunit of mitochondrial ATP synthase (ATP5B), disrupts the formation of ATP synthase complexes, and inhibits mitochondrial ATP synthesis. FUS expression activates the mitochondrial unfolded protein response (UPRmt). Importantly, down-regulating expression of ATP5B or UPRmt genes in FUS transgenic flies ameliorates neurodegenerative phenotypes. Our data show that mitochondrial impairment is a critical early event in FUS proteinopathy, and provide insights into the pathogenic mechanism of FUS-induced neurodegeneration.

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Stepenko, Yulia V., Veronika S. Shmigerova, Darya A. Kostina, Olesya V. Shcheblykina, Nina I. Zhernakova, Alexey V. Solin, Natalia V. Koroleva, Vera A. Markovskaya, Olga V. Dudnikova und Anton A. Bolgov. „Study of the neuroprotective properties of the heteroreceptor EPOR/CD131 agonist of peptide structure in tau-proteinopathy modeling“. Research Results in Pharmacology 10, Nr. 2 (17.06.2024): 41–47. http://dx.doi.org/10.18413/rrpharmacology.10.492.

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Introduction: Tau proteinopathy is a pathology associated with the activation of post-translational modifications and interactions of pathophysiological cascades of neuroinflammation with hyperphosphorylation of Tau aggregates. Therefore, preference is given to agents that have properties in reducing or slowing down the processes of neuroinflammation and post-translational modifications in the brain. Materials and Methods: The study was conducted on male and female homozygous individuals of a transgenic murine line with overexpression of mutant human Tau gene (P301S) and a background wild mouse line C57Bl/6J. To assess the progression of Tau proteinopathy, behavioral tests were used at two control time points, and the last one measured the level of neuroinflammation markers and tau-proteinopathy. Results and Discussion: In the group of P301S mice treated with ARA-290, an improvement in the phenotypic picture of Tau proteinopathy was demonstrated compared with intact animals. In the Barnes circular maze test, mice showed a decrease in the total distance traveled and the latent time spent on the platform, which indicates a rapid entry into the shelter. In the O-shaped maze test, the group maintained a fairly high level of spontaneous exploratory behavior. In the vertical rod test, the animals recorded the best time indicators that they needed to turn and maintain balance compared to the intact group. A statistically significant decrease in the level of GSK-3β and an increase in CDK5 and PP2A were revealed, which indicates a dephosphorylating effect on Tau protein, as well as markers of neuroinflammation. NF-KB and TNF-α were significantly reduced by 57% and 32%, respectively, compared to the intact group. Conclusion: In the model of transgenic P301S murine line with overexpression of the mutant human Tau gene, the peptide agonist of the EPOR/CD 131 heteroreceptor demonstrated neuroprotective properties, which were confirmed by indicators of behavioral tests and markers of neuroinflammation and tau-proteinopathy.

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Zheng, Qingwen, Huabo Su, Mark J. Ranek und Xuejun Wang. „Autophagy and p62 in Cardiac Proteinopathy“. Circulation Research 109, Nr. 3 (22.07.2011): 296–308. http://dx.doi.org/10.1161/circresaha.111.244707.

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10

Hasegawa, Masato, Tetsuaki Arai, Takashi Nonaka, Fuyuki Kametani, Mari Yoshida, Kenji Ikeda und Haruhiko Akiyama. „Proteomic analyses of TDP-43 proteinopathy“. Neuroscience Research 68 (Januar 2010): e35. http://dx.doi.org/10.1016/j.neures.2010.07.399.

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11

Forman, Mark S., John Q. Trojanowski und Virginia M.-Y. Lee. „TDP-43: a novel neurodegenerative proteinopathy“. Current Opinion in Neurobiology 17, Nr. 5 (Oktober 2007): 548–55. http://dx.doi.org/10.1016/j.conb.2007.08.005.

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12

Dhawan, P. S., B. P. Goodman, C. Toro, P. J. B. Dyck, C. Giannini und E. P. Bosch. „Fosmn Syndrome: a Tdp-43 proteinopathy?“ Journal of the Neurological Sciences 357 (Oktober 2015): e332. http://dx.doi.org/10.1016/j.jns.2015.08.1184.

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13

Cordts, Isabell, Annika Wachinger, Carlo Scialo, Paul Lingor, Magdalini Polymenidou, Emanuele Buratti und Emily Feneberg. „TDP-43 Proteinopathy Specific Biomarker Development“. Cells 12, Nr. 4 (12.02.2023): 597. http://dx.doi.org/10.3390/cells12040597.

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TDP-43 is the primary or secondary pathological hallmark of neurodegenerative diseases, such as amyotrophic lateral sclerosis, half of frontotemporal dementia cases, and limbic age-related TDP-43 encephalopathy, which clinically resembles Alzheimer’s dementia. In such diseases, a biomarker that can detect TDP-43 proteinopathy in life would help to stratify patients according to their definite diagnosis of pathology, rather than in clinical subgroups of uncertain pathology. Therapies developed to target pathological proteins that cause the disease a biomarker to detect and track the underlying pathology would greatly enhance such undertakings. This article reviews the latest developments and outlooks of deriving TDP-43-specific biomarkers from the pathophysiological processes involved in the development of TDP-43 proteinopathy and studies, using biosamples from clinical entities associated with TDP-43 pathology to investigate biomarker candidates.

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14

Hanna, S., K. Pankratz, A. Pham, Z. Dickey, A. Morrow, S. Voth, R. Morrow et al. „Klebsiella pneumoniae Isolated from Critically Ill Patient with Nosocomial Pneumonia Elicits a Proteinopathy“. American Journal of Clinical Pathology 162, Supplement_1 (Oktober 2024): S117. http://dx.doi.org/10.1093/ajcp/aqae129.260.

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Abstract Introduction/Objective Gram-negative opportunist Klebsiella pneumoniae has been identified by the World Health Organization as a critical threat partially due to its prevalence in nosocomial pneumonia. Survivors often suffer increased long-term morbidity and mortality secondary to end-organ damage, including impaired cognition. Pseudomonas aeruginosa lung infection generates an endothelial-derived tauopathy, yet whether K. pneumoniae infection elicits this phenomenon is unknown. We hypothesize K. pneumoniae infection triggers pathogenic tau release from endothelial cells, contributing to an infection-induced proteinopathy. Methods/Case Report We utilized wildtype, control, and tau-/- pulmonary microvascular endothelial cells (PMVECs). Tau was monitored via immunoblotting. K. pneumoniae (Kp 1-008) was isolated from the bronchoalveolar lavage of a critically ill patient diagnosed with a monomicrobial nosocomial pneumonia. Supernatants were filter-sterilized and boiled prior to transfer to naïve cells to determine transmissibility. Barrier permeability was assessed via transwell assays, cell viability through resazurin, and amyloid burden was monitored with Congo Red and Thioflavin T. Results (if a Case Study enter NA) Kp 1-008 infection induced permeability and tau release from control cells in a dose-dependent manner. Tau and amyloid burden increased over time in supernatants from control PMVECs. Sterile infection supernatants from control cells increased permeability and impaired oxidative metabolism in naïve cells whereas supernatants from tau-/- cells were markedly less pathogenic. Kp 1-008 induced proteinopathic cytotoxicity persisted strongly through two passages when derived from control cells but one passage when produced from tau-/- PMVECs. Conclusion Our results suggest that 1) K. pneumoniae infection of PMVECs generates a lung endothelial-derived proteinopathy and 2) endothelial tau is a significant contributor to its virulence.

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Bennett, Seth A., Samantha N. Cobos, Raven M. A. Fisher, Elizaveta Son, Rania Frederic, Rianna Segal, Huda Yousuf, Kaitlyn Chan, David K. Dansu und Mariana P. Torrente. „Direct and Indirect Protein Interactions Link FUS Aggregation to Histone Post-Translational Modification Dysregulation and Growth Suppression in an ALS/FTD Yeast Model“. Journal of Fungi 11, Nr. 1 (14.01.2025): 58. https://doi.org/10.3390/jof11010058.

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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are incurable neurodegenerative disorders sharing pathological and genetic features, including mutations in the FUS gene. FUS is an RNA-binding protein that mislocalizes to the cytoplasm and aggregates in ALS/FTD. In a yeast model, FUS proteinopathy is connected to changes in the epigenome, including reductions in the levels of H3S10ph, H3K14ac, and H3K56ac. Exploiting the same model, we reveal novel connections between FUS aggregation and epigenetic dysregulation. We show that the histone-modifying enzymes Ipl1 and Rtt109—responsible for installing H3S10ph and H3K56ac—are excluded from the nucleus in the context of FUS proteinopathy. Furthermore, we found that Ipl1 colocalizes with FUS, but does not bind it directly. We identified Nop1 and Rrp5, a histone methyltransferase and rRNA biogenesis protein, respectively, as FUS binding partners involved in the growth suppression phenotype connected to FUS proteinopathy. We propose that the nuclear exclusion of Ipl1 through indirect interaction with FUS drives the dysregulation of H3S10ph as well as H3K14ac via crosstalk. We found that the knockdown of Nop1 interferes with these processes. In a parallel mechanism, Rtt109 mislocalization results in reduced levels of H3K56ac. Our results highlight the contribution of epigenetic mechanisms to ALS/FTD and identify novel targets for possible therapeutic intervention.

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Li, Y., P. Ray, E. J. Rao, C. Shi, W. Guo, X. Chen, E. A. Woodruff, K. Fushimi und J. Y. Wu. „A Drosophila model for TDP-43 proteinopathy“. Proceedings of the National Academy of Sciences 107, Nr. 7 (26.01.2010): 3169–74. http://dx.doi.org/10.1073/pnas.0913602107.

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17

Josephs, Keith A., Janice L. Holton, Martin N. Rossor, Hans Braendgaard, Tetsutaro Ozawa, Nick C. Fox, Ronald C. Petersen et al. „Neurofilament inclusion body disease: a new proteinopathy?“ Brain 126, Nr. 10 (01.10.2003): 2291–303. http://dx.doi.org/10.1093/brain/awg231.

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18

Schattling, Benjamin, Jan Broder Engler, Constantin Volkmann, Nicola Rothammer, Marcel S. Woo, Meike Petersen, Iris Winkler et al. „Bassoon proteinopathy drives neurodegeneration in multiple sclerosis“. Nature Neuroscience 22, Nr. 6 (22.04.2019): 887–96. http://dx.doi.org/10.1038/s41593-019-0385-4.

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19

Zhang, Xiao, Satoshi Yamashita, Kentaro Hara, Tsukasa Doki, Nozomu Tawara, Tokunori Ikeda, Yohei Misumi et al. „A mutantMATR3mouse model to explain multisystem proteinopathy“. Journal of Pathology 249, Nr. 2 (18.06.2019): 182–92. http://dx.doi.org/10.1002/path.5289.

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20

Prakash, Amresh, Vijay Kumar, Naveen Kumar Meena und Andrew M. Lynn. „Elucidation of the structural stability and dynamics of heterogeneous intermediate ensembles in unfolding pathway of the N-terminal domain of TDP-43“. RSC Advances 8, Nr. 35 (2018): 19835–45. http://dx.doi.org/10.1039/c8ra03368d.

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21

Jamerlan, Angelo M., und Seong Soo A. An. „A Microplate-Based Approach to Map Interactions between TDP-43 and α-Synuclein“. Journal of Clinical Medicine 11, Nr. 3 (24.01.2022): 573. http://dx.doi.org/10.3390/jcm11030573.

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Trans-active response DNA-binding protein (TDP-43) is a multifunctional regulatory protein, whose abnormal deposition in neurons was linked to debilitating neurodegenerative diseases, such as amyotrophic lateral sclerosis, frontotemporal lobar degeneration, Limbic-predominant age-related TDP-43 encephalopathy, and Alzheimer’s disease with a secondary pathology. Several reports showed that TDP-43 proteinopathy as a comorbidity can form aggregates with other pathological proteins. The co-deposition of alpha synuclein and TDP-43 inclusions was previously reported in glial cells and by observing TDP-43 proteinopathy in Lewy body disease. In this study, it was hypothesized that alpha synuclein and TDP-43 may co-aggregate, resulting in comorbid synucleinopathy and TDP-43 proteinopathy. A solid-phase microplate-based immunoassay was used to map out the epitopes of anti-TDP-43 antibodies and locate the interaction of TDP-43 with α-synuclein. A region of the low complexity domain of TDP-43 (aa 311–314) was shown to interact with full-length α-synuclein. Conversely, full-length TDP-43 was shown to bind to the non-amyloid beta component of α-synuclein. Using in silico sequence-based prediction, the affinity and dissociation constant of full-length TDP-43 and α-synuclein were calculated to be −10.83 kcal/mol and 1.13 × 10−8, respectively. Taken together, this microplate-based method is convenient, economical, and rapid in locating antibody epitopes as well as interaction sites of two proteins.

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Kovacs, G. G., S. Klotz, P. Fischer, M. Hinterberger, G. Ricken, S. Hönigschnabl und E. Gelpi. „Complex Protein Astrogliopathy in an Octogenarian“. Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 48, s2 (Juli 2021): S10. http://dx.doi.org/10.1017/cjn.2021.169.

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Combination of multiple neurodegenerative proteinopathies is frequent in the elderly. We report the case of an octogenarian who attempted suicide and deceased after hospital admission. Anatomical mapping was performed in several cortical and subcortical brain regions using antibodies against phospho-tau, 4R tau, 3R tau, phospho-TDP-43, ubiquitin, α-synuclein, Aβ and p62. Unexpectedly, histopathologic examination showed prominent subpial, subependymal, grey and white matter, and perivascular aging-related tau astrogliopathy (ARTAG) affecting cortical and subcortical brain regions. This pathology was associated with intermediate Alzheimer’s disease neuropathologic change, cerebral amyloid angiopathy, Lewy-body-type and astroglial synuclein proteinopathy and a multiple system TDP-43 proteinopathy involving also the astroglia. This unusual case of extensive and widespread ARTAG with a complex multiproteinopathy may represent an independent disease entity in the elderly with tau astrogliopathy as the leading force.Learning ObjectiveRecognize astroglial protein deposits in neurodegeneration

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Skvortsova, V. I., S. O. Bachurin, A. A. Ustyugov, M. S. Kukharsky, A. V. Deikin, V. L. Buchman und N. N. Ninkina. „Gamma-Carbolines Derivatives As Promising Agents for the Development of Pathogenic Therapy for Proteinopathy“. Acta Naturae 10, Nr. 4 (15.12.2018): 59–62. http://dx.doi.org/10.32607/20758251-2018-10-4-59-62.

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Uncontrolled protein aggregation, accompanied by the formation of specific inclusions, is a major component of the pathogenesis of many common neurodegenerative diseases known as proteinopathies. The intermediate products of this aggregation are toxic to neurons and may be lethal. The development strategy of pathogenic therapy for proteinopathy is based on the design of drugs capable of both inhibiting proteinopathy progression and increasing the survival of affected neurons. The results of a decade-long research effort at leading Russian and international laboratories have demonstrated that Dimebon (Latrepirdine), as well as a number of its derivatives from a gamma-carboline group, show a strong neuroprotective effect and can modulate the course of a neurodegenerative process in both in vitro and in vivo model systems. The accumulated data indicate that gamma-carbolines are promising compounds for the development of pathogenic therapy for proteinopathies.

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Geula, Changiz, Rachel Keszycki, Pouya Jamshidi, Allegra Kawles, Grace Minogue, MargaretE Flanagan, ColleenR Zaccard, MMarsel Mesulam und Tamar Gefen. „Propagation of TDP-43 proteinopathy in neurodegenerative disorders“. Neural Regeneration Research 17, Nr. 7 (2022): 1498. http://dx.doi.org/10.4103/1673-5374.330609.

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Sharma, Chanchal, und Sang Ryong Kim. „Linking Oxidative Stress and Proteinopathy in Alzheimer’s Disease“. Antioxidants 10, Nr. 8 (30.07.2021): 1231. http://dx.doi.org/10.3390/antiox10081231.

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Proteinopathy and excessive production of reactive oxygen species (ROS), which are the principal features observed in the Alzheimer’s disease (AD) brain, contribute to neuronal toxicity. β-amyloid and tau are the primary proteins responsible for the proteinopathy (amyloidopathy and tauopathy, respectively) in AD, which depends on ROS production; these aggregates can also generate ROS. These mechanisms work in concert and reinforce each other to drive the pathology observed in the aging brain, which primarily involves oxidative stress (OS). This, in turn, triggers neurodegeneration due to the subsequent loss of synapses and neurons. Understanding these interactions may thus aid in the identification of potential neuroprotective therapies that could be clinically useful. Here, we review the role of β-amyloid and tau in the activation of ROS production. We then further discuss how free radicals can influence structural changes in key toxic intermediates and describe the putative mechanisms by which OS and oligomers cause neuronal death.

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Strong, Michael J., Sashi Kesavapany und Harish C. Pant. „The Pathobiology of Amyotrophic Lateral Sclerosis: A Proteinopathy?“ Journal of Neuropathology and Experimental Neurology 64, Nr. 8 (August 2005): 649–64. http://dx.doi.org/10.1097/01.jnen.0000173889.71434.ea.

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Kurucu, Hatice, Tara Spires-Jones und Colin Smith. „New terminology for a common TDP-43 proteinopathy“. Lancet Neurology 18, Nr. 8 (August 2019): 714–15. http://dx.doi.org/10.1016/s1474-4422(19)30223-6.

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Cook, Casey N., Yanwei Wu, Hana M. Odeh, Tania F. Gendron, Karen Jansen-West, Giulia del Rosso, Mei Yue et al. „C9orf72 poly(GR) aggregation induces TDP-43 proteinopathy“. Science Translational Medicine 12, Nr. 559 (02.09.2020): eabb3774. http://dx.doi.org/10.1126/scitranslmed.abb3774.

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TAR DNA-binding protein 43 (TDP-43) inclusions are a pathological hallmark of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), including cases caused by G4C2 repeat expansions in the C9orf72 gene (c9FTD/ALS). Providing mechanistic insight into the link between C9orf72 mutations and TDP-43 pathology, we demonstrated that a glycine-arginine repeat protein [poly(GR)] translated from expanded G4C2 repeats was sufficient to promote aggregation of endogenous TDP-43. In particular, toxic poly(GR) proteins mediated sequestration of full-length TDP-43 in an RNA-independent manner to induce cytoplasmic TDP-43 inclusion formation. Moreover, in GFP-(GR)200 mice, poly(GR) caused the mislocalization of nucleocytoplasmic transport factors and nuclear pore complex proteins. These mislocalization events resulted in the aberrant accumulation of endogenous TDP-43 in the cytoplasm where it co-aggregated with poly(GR). Last, we demonstrated that treating G4C2 repeat–expressing mice with repeat-targeting antisense oligonucleotides lowered poly(GR) burden, which was accompanied by reduced TDP-43 pathology and neurodegeneration, including lowering of plasma neurofilament light (NFL) concentration. These results contribute to clarification of the mechanism by which poly(GR) drives TDP-43 proteinopathy, confirm that G4C2-targeted therapeutics reduce TDP-43 pathology in vivo, and demonstrate that alterations in plasma NFL provide insight into the therapeutic efficacy of disease-modifying treatments.

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Fernández-Tresguerres, M. Elena, Susana Moreno-Díaz de la Espina, Fátima Gasset-Rosa und Rafael Giraldo. „A DNA-promoted amyloid proteinopathy in Escherichia coli“. Molecular Microbiology 77, Nr. 6 (September 2010): 1456–69. http://dx.doi.org/10.1111/j.1365-2958.2010.07299.x.

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Gao, Ju, Luwen Wang, Tingxiang Yan, George Perry und Xinglong Wang. „TDP-43 proteinopathy and mitochondrial abnormalities in neurodegeneration“. Molecular and Cellular Neuroscience 100 (Oktober 2019): 103396. http://dx.doi.org/10.1016/j.mcn.2019.103396.

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Rezvykh, Alexander, Daniil Shteinberg, Evgeny Bronovitsky, Aleksey Ustyugov und Sergei Funikov. „Animal Models of FUS-Proteinopathy: A Systematic Review“. Biochemistry (Moscow) 89, S1 (Januar 2024): S34—S56. http://dx.doi.org/10.1134/s0006297924140037.

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Chae, Juhee, Sung-Hye Park und Jung-Joon Sung. „VCP-related Multisystem Proteinopathy Presenting with Lobulated Myofibers“. Korean Journal of Neuromuscular Disorders 16, Nr. 1 (30.06.2024): 17–19. http://dx.doi.org/10.46518/kjnmd.2024.16.1.17.

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Valosin-containing protein (VCP)-related multisystem proteinopathy (MSP1) is a rare genetic disorder marked by abnormal protein accumulation. This study presents the case of a 52-year-old woman with MSP1, showing progressive weakness, gait disturbances, and respiratory muscle weakness over five years. The clinical examination revealed diverse presentations, including neurogenic changes in electrophysiologic study, multifocal fatty changes of muscle, and cognitive impairment with a confirmed VCP gene mutation through genetic testing. Notably, we identified lobulated myofibers in the muscle biopsy, an unusual finding in MSP1. This is the first report of lobulated myofibers in MSP1 with multisystem involvement. Identifying unique muscle biopsy results in suspected MSP1 patients through careful neurological examinations and timely genetic testing may help in early diagnosis and appropriate management.

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Termsarasab, Pichet, Thananan Thammongkolchai, Ju Gao, Luwen Wang, Jingjing Liang und Xinglong Wang. „Cytoplasmic mislocalization and mitochondrial colocalization of TDP-43 are common features between normal aged and young mice“. Experimental Biology and Medicine 245, Nr. 17 (25.03.2020): 1584–93. http://dx.doi.org/10.1177/1535370220914253.

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Transactive response DNA binding protein 43 (TDP-43) pathologies have been well recognized in various neurodegenerative disorders including frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and Alzheimer’s disease (AD). However, there have been limited studies on whether there are any TDP-43 alterations in normal aging. We investigated TDP-43 distribution in different brain regions in normal aged ( n = 3 for 26- or 36-month-old) compared to young ( n = 3 for 6- or 12-month-old) mice. In both normal aged and young mice, TDP-43 and phosphorylated TDP-43 (pTDP-43) demonstrated a unique pattern of distribution in neurons in some specific brain regions including the pontine nuclei, thalamus, CA3 region of the hippocampus, and orbital cortex. This pattern was demonstrated on higher magnification of high-resolution double fluorescence images and confocal microscopy as mislocalization of TDP-43 and pTDP-43, characterized by neuronal nuclear depletion and cytoplasmic accumulation in these brain regions, as well as colocalization between TDP-43 or pTDP-43 and mitochondria, similar to what has been described previously in neurodegenerative disorders. All these findings were identical in both normal aged and young mice. In summary, TDP-43 and pTDP-43 mislocalization from nucleus to cytoplasm and their colocalization with mitochondria in the specific brain regions are present not only in aging, but also in young healthy states. Our findings provide a new insight for the role of TDP-43 proteinopathy in health and diseases, and that aging may not be a critical factor for the development of TDP-43 proteinopathy in subpopulations of neurons. Impact statement Despite increasing evidence implicating the important role of TDP-43 in the pathogenesis of a wide range of age-related neurodegenerative diseases, there is limited study of TDP-43 proteinopathy and its association with mitochondria during normal aging. Our findings of cytoplasmic accumulation of TDP-43 that is highly colocalized with mitochondria in neurons in selective brain regions in young animals in the absence of neuronal loss provide a novel insight into the development of TDP-43 proteinopathy and its contribution to neuronal loss.

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Clarke, Jennifer, Can Kayatekin, Catherine Viel, Lamya Shihabuddin und Sergio Pablo Sardi. „Murine Models of Lysosomal Storage Diseases Exhibit Differences in Brain Protein Aggregation and Neuroinflammation“. Biomedicines 9, Nr. 5 (21.04.2021): 446. http://dx.doi.org/10.3390/biomedicines9050446.

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Genetic, epidemiological and experimental evidence implicate lysosomal dysfunction in Parkinson’s disease (PD) and related synucleinopathies. Investigate several mouse models of lysosomal storage diseases (LSDs) and evaluate pathologies reminiscent of synucleinopathies. We obtained brain tissue from symptomatic mouse models of Gaucher, Fabry, Sandhoff, Niemann–Pick A (NPA), Hurler, Pompe and Niemann–Pick C (NPC) diseases and assessed for the presence of Lewy body-like pathology (proteinase K-resistant α-synuclein and tau aggregates) and neuroinflammation (microglial Iba1 and astrocytic GFAP) by immunofluorescence. All seven LSD models exhibited evidence of proteinopathy and/or inflammation in the central nervous system (CNS). However, these phenotypes were divergent. Gaucher and Fabry mouse models displayed proteinase K-resistant α-synuclein and tau aggregates but no neuroinflammation; whereas Sandhoff, NPA and NPC showed marked neuroinflammation and no overt proteinopathy. Pompe disease animals uniquely displayed widespread distribution of tau aggregates accompanied by moderate microglial activation. Hurler mice also demonstrated proteinopathy and microglial activation. The present study demonstrated additional links between LSDs and pathogenic phenotypes that are hallmarks of synucleinopathies. The data suggest that lysosomal dysregulation can contribute to brain region-specific protein aggregation and induce widespread neuroinflammation in the brain. However, only a few LSD models examined exhibited phenotypes consistent with synucleinopathies. While no model can recapitulate the complexity of PD, they can enable the study of specific pathways and mechanisms contributing to disease pathophysiology. The present study provides evidence that there are existing, previously unutilized mouse models that can be employed to study pathogenic mechanisms and gain insights into potential PD subtypes, helping to determine if they are amenable to pathway-specific therapeutic interventions.

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Modgil, Shweta, Radhika Khosla, Abha Tiwari, Kaushal Sharma und Akshay Anand. „Association of Plasma Biomarkers for Angiogenesis and Proteinopathy in Indian Amyotrophic Lateral Sclerosis Patients“. Journal of Neurosciences in Rural Practice 11, Nr. 04 (20.08.2020): 573–80. http://dx.doi.org/10.1055/s-0040-1714314.

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Abstarct Background Amyotrophic lateral sclerosis (ALS) is a rare motor neuron disease with progressive degeneration of motor neurons. Various molecules have been explored to provide the early diagnostic/prognostic tool for ALS without getting much success in the field and miscellaneous reports studied in various population. Objective The study was aimed to see the differential expression of proteins involved in angiogenesis (angiogenin [ANG], vascular endothelial growth factor [VEGF], vascular endothelial growth factor receptor 2 [VEGFR2], etc), proteinopathy (transactive response DNA binding protein-43 [TDP-43] and optineurin [OPTN]), and neuroinflammation (monocyte chemoattractant protein-1[MCP-1]) based on the characteristics of ALS pathology. Though, suitable panel based on protein expression profile can be designed to robust the ALS identification by enhancing the prognostic and diagnostic efficacy for ALS. Methods A total of 89 ALS patients and 98 nonneurological controls were analyzed for the protein expression. Expression of angiogenic (VEGF, VEGFR2, and ANG), neuroinflammation (MCP-1), and proteinopathy (TDP-43 and OPTN) markers were estimated in plasma of the participants. Proteins were normalized with respective value of total protein before employing statistical analysis. Results Analysis has exhibited significantly reduced expression of angiogenic, proteinopathy, and neuroinflammation biomarkers in ALS patients in comparison to controls. Spearman’s correlation analysis has showed the positive correlation to each protein. Conclusion Altered expression of these proteins is indicating the prominent function in ALS pathology which may be interdependent and may have a synergistic role. Hence, a panel of expression can be proposed to diagnose ALS patient which may also suggest the modulation of therapeutic strategy according to expression profile of patient.

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Gauthreaux, Kathryn M., Merilee A. Teylan, Yuriko Katsumata, Charles Mock, Jessica E. Culhane, Yen-Chi Chen, Kwun C. G. Chan et al. „Limbic-Predominant Age-Related TDP-43 Encephalopathy“. Neurology 98, Nr. 14 (04.02.2022): e1422-e1433. http://dx.doi.org/10.1212/wnl.0000000000200001.

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Background and ObjectivesLimbic-predominant age-related Tar DNA binding protein 43 (TDP-43) encephalopathy neuropathologic change (LATE-NC) is present in ≈25% of older persons' brains and is strongly associated with cognitive impairment. Hippocampal sclerosis (HS) pathology is often comorbid with LATE-NC, but the clinical and pathologic correlates of HS in LATE-NC are not well understood.MethodsThis retrospective autopsy cohort study used data derived from the National Alzheimer's Coordinating Center Neuropathology Data Set, which included neurologic status, medical histories, and neuropathologic results. All autopsies were performed in 2014 or later. Among participants with LATE-NC, those who also had HS pathology were compared with those without HS with regard to candidate risk factors or common underlying diseases. Statistical significance was set at nominal p < 0.05 in this exploratory study.ResultsA total of 408 participants were included (n = 221 were LATE-NC+/HS−, n = 145 were LATE-NC+/HS+, and n = 42 were LATE-NC−/HS+). Most of the included LATE-NC+ participants were severely impaired cognitively (83.3% with dementia). Compared to HS− participants, LATE-NC+ participants with HS trended toward having worse cognitive status and scored lower on the Personal Care and Orientation domains (both p = 0.03). Among LATE-NC+ participants with Braak neurofibrillary tangle (NFT) stages 0 to IV (n = 88), HS+ participants were more impaired in the Memory and Orientation domains (both p = 0.02). There were no differences (HS+ compared with HS−) in the proportion with clinical histories of seizures, stroke, cardiac bypass procedures, diabetes, or hypertension. The HS+ group lacking TDP-43 proteinopathy (n = 42) was relatively likely to have had strokes (p = 0.03). When LATE-NC+ participants with or without HS were compared, there were no differences in Alzheimer disease neuropathologies (Thal β-amyloid phases or Braak NFT stages) or Lewy body pathologies. However, the HS+ group was less likely to have amygdala-restricted TDP-43 proteinopathy (LATE-NC stage 1) and more likely to have neocortical TDP-43 proteinopathy (LATE-NC stage 3) (p < 0.001). LATE-NC+ brains with HS also tended to have more severe circle of Willis atherosclerosis and arteriolosclerosis pathologies.DiscussionIn this cohort skewed toward participants with severe dementia, LATE-NC+ HS pathology was not associated with seizures or with Alzheimer-type pathologies. Rather, the presence of comorbid HS pathology was associated with more widespread TDP-43 proteinopathy and with more severe non–β-amyloid vessel wall pathologies.

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Tsuji, Hiroshi, Tetsuaki Arai, Fuyuki Kametani, Takashi Nonaka, Makiko Yamashita, Masami Suzukake, Masato Hosokawa et al. „Molecular analysis and biochemical classification of TDP-43 proteinopathy“. Brain 135, Nr. 11 (03.10.2012): 3380–91. http://dx.doi.org/10.1093/brain/aws230.

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Masaki, Katsuhisa, Yoshifumi Sonobe, Ghanashyam Ghadge, Peter Pytel und Raymond P. Roos. „TDP-43 proteinopathy in Theiler’s murine encephalomyelitis virus infection“. PLOS Pathogens 15, Nr. 2 (11.02.2019): e1007574. http://dx.doi.org/10.1371/journal.ppat.1007574.

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Mishima, Takayasu, Shunsuke Koga, Wen-Lang Lin, Koji Kasanuki, Monica Castanedes-Casey, Zbigniew K. Wszolek, Shin J. Oh, Yoshio Tsuboi und Dennis W. Dickson. „Perry Syndrome: A Distinctive Type of TDP-43 Proteinopathy“. Journal of Neuropathology & Experimental Neurology 76, Nr. 8 (14.07.2017): 676–82. http://dx.doi.org/10.1093/jnen/nlx049.

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Benatar, M., J. Wuu, C. Fernandez, C. C. Weihl, H. Katzen, J. Steele, B. Oskarsson und J. P. Taylor. „Motor neuron involvement in multisystem proteinopathy: Implications for ALS“. Neurology 80, Nr. 20 (01.05.2013): 1874–80. http://dx.doi.org/10.1212/wnl.0b013e3182929fc3.

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Pievani, Michela, Nicola Filippini, Martijn P. van den Heuvel, Stefano F. Cappa und Giovanni B. Frisoni. „Brain connectivity in neurodegenerative diseases—from phenotype to proteinopathy“. Nature Reviews Neurology 10, Nr. 11 (07.10.2014): 620–33. http://dx.doi.org/10.1038/nrneurol.2014.178.

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De Ridder, Willem, Abdelkrim Azmi, Christoph S. Clemen, Ludwig Eichinger, Andreas Hofmann, Rolf Schröder, Katherine Johnson et al. „Multisystem proteinopathy due to a homozygous p.Arg159His VCP mutation“. Neurology 94, Nr. 8 (17.12.2019): e785-e796. http://dx.doi.org/10.1212/wnl.0000000000008763.

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ObjectiveTo assess the clinical, radiologic, myopathologic, and proteomic findings in a patient manifesting a multisystem proteinopathy due to a homozygous valosin-containing protein gene (VCP) mutation previously reported to be pathogenic in the heterozygous state.MethodsWe studied a 36-year-old male index patient and his father, both presenting with progressive limb-girdle weakness. Muscle involvement was assessed by MRI and muscle biopsies. We performed whole-exome sequencing and Sanger sequencing for segregation analysis of the identified p.Arg159His VCP mutation. To dissect biological disease signatures, we applied state-of-the-art quantitative proteomics on muscle tissue of the index case, his father, 3 additional patients with VCP-related myopathy, and 3 control individuals.ResultsThe index patient, homozygous for the known p.Arg159His mutation in VCP, manifested a typical VCP-related myopathy phenotype, although with a markedly high creatine kinase value and a relatively early disease onset, and Paget disease of bone. The father exhibited a myopathy phenotype and discrete parkinsonism, and multiple deceased family members on the maternal side of the pedigree displayed a dementia, parkinsonism, or myopathy phenotype. Bioinformatic analysis of quantitative proteomic data revealed the degenerative nature of the disease, with evidence suggesting selective failure of muscle regeneration and stress granule dyshomeostasis.ConclusionWe report a patient showing a multisystem proteinopathy due to a homozygous VCP mutation. The patient manifests a severe phenotype, yet fundamental disease characteristics are preserved. Proteomic findings provide further insights into VCP-related pathomechanisms.

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Liscic, R. M., L. T. Grinberg, J. Zidar, M. A. Gitcho und N. J. Cairns. „ALS and FTLD: two faces of TDP-43 proteinopathy“. European Journal of Neurology 15, Nr. 8 (August 2008): 772–80. http://dx.doi.org/10.1111/j.1468-1331.2008.02195.x.

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Zhang, Jiasheng, Dmitry Velmeshev, Kei Hashimoto, Yu-Hsin Huang, Jeffrey W. Hofmann, Xiaoyu Shi, Jiapei Chen et al. „Neurotoxic microglia promote TDP-43 proteinopathy in progranulin deficiency“. Nature 588, Nr. 7838 (31.08.2020): 459–65. http://dx.doi.org/10.1038/s41586-020-2709-7.

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Al-Tahan, Sejad, Ebaa Al-Obeidi, Hiroshi Yoshioka, Anita Lakatos, Lan Weiss, Marjorie Grafe, Johanna Palmio et al. „Novel valosin-containing protein mutations associated with multisystem proteinopathy“. Neuromuscular Disorders 28, Nr. 6 (Juni 2018): 491–501. http://dx.doi.org/10.1016/j.nmd.2018.04.007.

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Fernández‐Sáiz, Vanesa, und Alexander Buchberger. „Imbalances in p97 co‐factor interactions in human proteinopathy“. EMBO reports 11, Nr. 6 (23.04.2010): 479–85. http://dx.doi.org/10.1038/embor.2010.49.

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Wider, C., D. Dickson, D. Calne, J. Stoessl, L. Gutmann, S. Calne, L. Brown und Z. Wszolek. „2.012 Perry's syndrome is a unique TDP-43 proteinopathy“. Parkinsonism & Related Disorders 13 (Januar 2007): S88—S89. http://dx.doi.org/10.1016/s1353-8020(08)70580-7.

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Wider, C., D. Dickson, D. Calne, J. Stoessl, L. Gutmann, S. Calne, L. Brown und Z. Wszolek. „2.115 Perry's syndrome is a unique TDP-43 proteinopathy“. Parkinsonism & Related Disorders 13 (Januar 2007): S96. http://dx.doi.org/10.1016/s1353-8020(08)70607-2.

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Gelpi, E., J. van der Zee, A. Turon Estrada, C. Van Broeckhoven und R. Sanchez-Valle. „TARDBPmutation p.Ile383Val associated with semantic dementia and complex proteinopathy“. Neuropathology and Applied Neurobiology 40, Nr. 2 (21.01.2014): 225–30. http://dx.doi.org/10.1111/nan.12063.

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Kawakami, Ito, Tetsuaki Arai und Masato Hasegawa. „The basis of clinicopathological heterogeneity in TDP-43 proteinopathy“. Acta Neuropathologica 138, Nr. 5 (26.09.2019): 751–70. http://dx.doi.org/10.1007/s00401-019-02077-x.

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Abstract Transactive response DNA-binding protein 43 kDa (TDP-43) was identified as a major disease-associated component in the brain of patients with amyotrophic lateral sclerosis (ALS), as well as the largest subset of patients with frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U), which characteristically exhibits cytoplasmic inclusions that are positive for ubiquitin but negative for tau and α-synuclein. TDP-43 pathology occurs in distinct brain regions, involves disparate brain networks, and features accumulation of misfolded proteins in various cell types and in different neuroanatomical regions. The clinical phenotypes of ALS and FTLD-TDP (FTLD with abnormal intracellular accumulations of TDP-43) correlate with characteristic distribution patterns of the underlying pathology across specific brain regions with disease progression. Recent studies support the idea that pathological protein spreads from neuron to neuron via axonal transport in a hierarchical manner. However, little is known to date about the basis of the selective cellular and regional vulnerability, although the information would have important implications for the development of targeted and personalized therapies. Here, we aim to summarize recent advances in the neuropathology, genetics and animal models of TDP-43 proteinopathy, and their relationship to clinical phenotypes for the underlying selective neuronal and regional susceptibilities. Finally, we attempt to integrate these findings into the emerging picture of TDP-43 proteinopathy, and to highlight key issues for future therapy and research.

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