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1
Hill, Sarah J., Daniel A. Mordes, Lisa A. Cameron, Donna S. Neuberg, Serena Landini, Kevin Eggan et David M. Livingston. « Two familial ALS proteins function in prevention/repair of transcription-associated DNA damage ». Proceedings of the National Academy of Sciences 113, no 48 (14 novembre 2016) : E7701—E7709. http://dx.doi.org/10.1073/pnas.1611673113.
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Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron dysfunction disease that leads to paralysis and death. There is currently no established molecular pathogenesis pathway. Multiple proteins involved in RNA processing are linked to ALS, including FUS and TDP43, and we propose a disease mechanism in which loss of function of at least one of these proteins leads to an accumulation of transcription-associated DNA damage contributing to motor neuron cell death and progressive neurological symptoms. In support of this hypothesis, we find that FUS or TDP43 depletion leads to increased sensitivity to a transcription-arresting agent due to increased DNA damage. Thus, these proteins normally contribute to the prevention or repair of transcription-associated DNA damage. In addition, both FUS and TDP43 colocalize with active RNA polymerase II at sites of DNA damage along with the DNA damage repair protein, BRCA1, and FUS and TDP43 participate in the prevention or repair of R loop-associated DNA damage, a manifestation of aberrant transcription and/or RNA processing. Gaining a better understanding of the role(s) that FUS and TDP43 play in transcription-associated DNA damage could shed light on the mechanisms underlying ALS pathogenesis.
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Luo, Jiayi, et Paul M. Harrison. « Evolution of sequence traits of prion-like proteins linked to amyotrophic lateral sclerosis (ALS) ». PeerJ 10 (17 novembre 2022) : e14417. http://dx.doi.org/10.7717/peerj.14417.
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Prions are proteinaceous particles that can propagate an alternative conformation to further copies of the same protein. They have been described in mammals, fungi, bacteria and archaea. Furthermore, across diverse organisms from bacteria to eukaryotes, prion-like proteins that have similar sequence characters are evident. Such prion-like proteins have been linked to pathomechanisms of amyotrophic lateral sclerosis (ALS) in humans, in particular TDP43, FUS, TAF15, EWSR1 and hnRNPA2. Because of the desire to study human disease-linked proteins in model organisms, and to gain insights into the functionally important parts of these proteins and how they have changed across hundreds of millions of years of evolution, we analyzed how the sequence traits of these five proteins have evolved across eukaryotes, including plants and metazoa. We discover that the RNA-binding domain architecture of these proteins is deeply conserved since their emergence. Prion-like regions are also deeply and widely conserved since the origination of the protein families for FUS, TAF15 and EWSR1, and since the last common ancestor of metazoa for TDP43 and hnRNPA2. Prion-like composition is uncommon or weak in any plant orthologs observed, however in TDP43 many plant proteins have equivalent regions rich in other amino acids (namely glycine and tyrosine and/or serine) that may be linked to stress granule recruitment. Deeply conserved low-complexity domains are identified that likely have functional significance.
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Laudanski, Krzysztof, Jihane Hajj, Mariana Restrepo, Kumal Siddiq, Tony Okeke et Daniel J. Rader. « Dynamic Changes in Central and Peripheral Neuro-Injury vs. Neuroprotective Serum Markers in COVID-19 Are Modulated by Different Types of Anti-Viral Treatments but Do Not Affect the Incidence of Late and Early Strokes ». Biomedicines 9, no 12 (29 novembre 2021) : 1791. http://dx.doi.org/10.3390/biomedicines9121791.
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The balance between neurodegeneration, neuroinflammation, neuroprotection, and COVID-19-directed therapy may underly the heterogeneity of SARS-CoV-2′s neurological outcomes. A total of 105 patients hospitalized with a diagnosis of COVID-19 had serum collected over a 6 month period to assess neuroinflammatory (MIF, CCL23, MCP-1), neuro-injury (NFL, NCAM-1), neurodegenerative (KLK6, τ, phospho τ, amyloids, TDP43, YKL40), and neuroprotective (clusterin, fetuin, TREM-2) proteins. These were compared to markers of nonspecific inflammatory responses (IL-6, D-dimer, CRP) and of the overall viral burden (spike protein). Data regarding treatment (steroids, convalescent plasma, remdasavir), pre-existing conditions, and incidences of strokes were collected. Amyloid β42, TDP43, NF-L, and KLK6 serum levels declined 2–3 days post-admission, yet recovered to admission baseline levels by 7 days. YKL-40 and NCAM-1 levels remained elevated over time, with clusters of differential responses identified among TREM-2, TDP43, and YKL40. Fetuin was elevated after the onset of COVID-19 while TREM-2 initially declined before significantly increasing over time. MIF serum level was increased 3–7 days after admission. Ferritin correlated with TDP-43 and KLK6. No treatment with remdesivir coincided with elevations in Amyloid-β40. A lack of convalescent plasma resulted in increased NCAM-1 and total tau, and steroidal treatments did not significantly affect any markers. A total of 11 incidences of stroke were registered up to six months after initial admission for COVID-19. Elevated D-dimer, platelet counts, IL-6, and leukopenia were observed. Variable MIF serum levels differentiated patients with CVA from those who did not have a stroke during the acute phase of COVID-19. This study demonstrated concomitant and opposite changes in neurodegenerative and neuroprotective markers persisting well into recovery.
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Carter, G. Campbell, Chia-Heng Hsiung, Leman Simpson, Haopeng Yang et Xin Zhang. « N-terminal Domain of TDP43 Enhances Liquid-Liquid Phase Separation of Globular Proteins ». Journal of Molecular Biology 433, no 10 (mai 2021) : 166948. http://dx.doi.org/10.1016/j.jmb.2021.166948.
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Raghunathan, Rekha, Kathleen Turajane et Li Chin Wong. « Biomarkers in Neurodegenerative Diseases : Proteomics Spotlight on ALS and Parkinson’s Disease ». International Journal of Molecular Sciences 23, no 16 (18 août 2022) : 9299. http://dx.doi.org/10.3390/ijms23169299.
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Neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD) are both characterized by pathogenic protein aggregates that correlate with the progressive degeneration of neurons and the loss of behavioral functions. Both diseases lack biomarkers for diagnosis and treatment efficacy. Proteomics is an unbiased quantitative tool capable of the high throughput quantitation of thousands of proteins from minimal sample volumes. We review recent proteomic studies in human tissues, plasma, cerebrospinal fluid (CSF), and exosomes in ALS and PD that identify proteins with potential utility as biomarkers. Further, we review disease-related post-translational modifications in key proteins TDP43 in ALS and α-synuclein in PD studies, which may serve as biomarkers. We compare relative and absolute quantitative proteomic approaches in key biomarker studies in ALS and PD and discuss recent technological advancements which may identify suitable biomarkers for the early-diagnosis treatment efficacy of these diseases.
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Tanaka, Hikari, et Hitoshi Okazawa. « PQBP1 : The Key to Intellectual Disability, Neurodegenerative Diseases, and Innate Immunity ». International Journal of Molecular Sciences 23, no 11 (2 juin 2022) : 6227. http://dx.doi.org/10.3390/ijms23116227.
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The idea that a common pathology underlies various neurodegenerative diseases and dementias has attracted considerable attention in the basic and medical sciences. Polyglutamine binding protein-1 (PQBP1) was identified in 1998 after a molecule was predicted to bind to polyglutamine tract amino acid sequences, which are associated with a family of neurodegenerative disorders called polyglutamine diseases. Hereditary gene mutations of PQBP1 cause intellectual disability, whereas acquired loss of function of PQBP1 contributes to dementia pathology. PQBP1 functions in innate immune cells as an intracellular receptor that recognizes pathogens and neurodegenerative proteins. It is an intrinsically disordered protein that generates intracellular foci, similar to other neurodegenerative disease proteins such as TDP43, FUS, and hnRNPs. The knowledge accumulated over more than 20 years has given rise to a new concept that shifts in the equilibrium between physiological and pathological processes have their basis in the dysregulation of common protein structure-linked molecular mechanisms.
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Lee, Yichen, Bo H. Lee, William Yip, Pingchen Chou et Bak-Sau Yip. « Neurofilament Proteins as Prognostic Biomarkers in Neurological Disorders ». Current Pharmaceutical Design 25, no 43 (9 janvier 2020) : 4560–69. http://dx.doi.org/10.2174/1381612825666191210154535.
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Neurofilaments: light, medium, and heavy (abbreviated as NF-L, NF-M, and NF-H, respectively), which belong to Type IV intermediate filament family (IF), are neuron-specific cytoskeletal components. Neurofilaments are axonal structural components and integral components of synapses, which are important for neuronal electric signal transmissions along the axons and post-translational modification. Abnormal assembly of neurofilaments is found in several human neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), infantile spinal muscular atrophy (SMA), and hereditary sensory-motor neuropathy (HSMN). In addition, those pathological neurofilament accumulations are known in α-synuclein in Parkinson’s disease (PD), Aβ and tau in Alzheimer’s disease (AD), polyglutamine in CAG trinucleotide repeat disorders, superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP43), neuronal FUS proteins, optineurin (OPTN), ubiquilin 2 (UBQLN2), and dipeptide repeat protein (DRP) in amyotrophic lateral sclerosis (ALS). When axon damage occurs in central nervous disorders, neurofilament proteins are released and delivered into cerebrospinal fluid (CSF), which are then circulated into blood. New quantitative analyses and assay techniques are well-developed for the detection of neurofilament proteins, particularly NF-L and the phosphorylated NF-H (pNF-H) in CSF and serum. This review discusses the potential of using peripheral blood NF quantities and evaluating the severity of damage in the nervous system. Intermediate filaments could be promising biomarkers for evaluating disease progression in different nervous system disorders.
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Jiang, Tianlin, Jiahua Wang, Chao Li, Guiyun Cao et Xiaohong Wang. « Prohibitins : A Key Link between Mitochondria and Nervous System Diseases ». Oxidative Medicine and Cellular Longevity 2022 (8 juillet 2022) : 1–13. http://dx.doi.org/10.1155/2022/7494863.
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Prohibitins (PHBs) are conserved proteins in eukaryotic cells, which are mainly located in the inner mitochondrial membrane (IMM), cell nucleus, and cell membrane. PHBs play crucial roles in various cellular functions, including the cell cycle regulation, tumor suppression, immunoglobulin M receptor binding, and aging. In addition, recent in vitro and in vivo studies have revealed that PHBs are important in nervous system diseases. PHBs can prevent apoptosis, inflammation, mitochondrial dysfunction, and autophagy in neurological disorders through different molecules and pathways, such as OPA-1, PINK1/Parkin, IL6/STAT3, Tau, NO, LC3, and TDP43. Therefore, PHBs show great promise in the protection of neurological disorders. This review summarizes the relevant studies on the relationship between PHBs and neurological disorders and provides an update on the molecular mechanisms of PHBs in nervous system diseases.
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Tang, Fu-Lei, Lu Zhao, Yang Zhao, Dong Sun, Xiao-Juan Zhu, Lin Mei et Wen-Cheng Xiong. « Coupling of terminal differentiation deficit with neurodegenerative pathology in Vps35-deficient pyramidal neurons ». Cell Death & ; Differentiation 27, no 7 (6 janvier 2020) : 2099–116. http://dx.doi.org/10.1038/s41418-019-0487-2.
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AbstractVps35 (vacuolar protein sorting 35) is a key component of retromer that regulates transmembrane protein trafficking. Dysfunctional Vps35 is a risk factor for neurodegenerative diseases, including Parkinson’s and Alzheimer’s diseases. Vps35 is highly expressed in developing pyramidal neurons, and its physiological role in developing neurons remains to be explored. Here, we provide evidence that Vps35 in embryonic neurons is necessary for axonal and dendritic terminal differentiation. Loss of Vps35 in embryonic neurons results in not only terminal differentiation deficits, but also neurodegenerative pathology, such as cortical brain atrophy and reactive glial responses. The atrophy of neocortex appears to be in association with increases in neuronal death, autophagosome proteins (LC3-II and P62), and neurodegeneration associated proteins (TDP43 and ubiquitin-conjugated proteins). Further studies reveal an increase of retromer cargo protein, sortilin1 (Sort1), in lysosomes of Vps35-KO neurons, and lysosomal dysfunction. Suppression of Sort1 diminishes Vps35-KO-induced dendritic defects. Expression of lysosomal Sort1 recapitulates Vps35-KO-induced phenotypes. Together, these results demonstrate embryonic neuronal Vps35’s function in terminal axonal and dendritic differentiation, reveal an association of terminal differentiation deficit with neurodegenerative pathology, and uncover an important lysosomal contribution to both events.
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Miguelez-Rodriguez, Aitzol, Jorge Santos-Juanes, Ikerne Vicente-Etxenausia, Katty Perez de Heredia-Goñi, Beatriz Garcia, Luis M. Quiros, Laura Lorente-Gea, Isabel Guerra-Merino, Jose J. Aguirre et Ivan Fernandez-Vega. « Brains with sporadic Creutzfeldt-Jakob disease and copathology showed a prolonged end-stage of disease ». Journal of Clinical Pathology 71, no 5 (2 novembre 2017) : 446–50. http://dx.doi.org/10.1136/jclinpath-2017-204794.
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AimsTo investigate the expression of major proteins related to primary neurodegenerative diseases and their prognostic significance in brains with Creutzfeldt-Jakob disease (CJD).Materials and methodsThirty consecutive cases of confirmed CJD during the period 2010–2015 at Basque Brain bank were retrospectively reviewed. Moreover, major neurodegenerative-associated proteins (phosphorylated Tau, 4R tau, 3R tau, alpha-synuclein, TDP43, amyloid beta) were tested. Clinical data were reviewed. Cases were divided according to the presence or absence of copathology. Survival curves were also determined.ResultsCopathology was significantly associated with survival in brains with CJD (4.2±1.2 vs 9.2±1.9; P=0.019) and in brains with MM1/MV1 CJD (2.1±1.0 vs 6.7±2.8; P=0.012). Besides, the presence of more than one major neurodegenerative-associated protein was significantly associated with survival (4.2±1.2 vs 10.7±2.6; P=0.017). Thus, univariate analyses further pointed out variables significantly associated with better survival: copathology in CJD (HR=0.430; P=0.033); more than one neurodegenerative-associated protein in CJD (HR=0.369; P=0.036) and copathology in MM1/MV1 CJD (HR=0.525; P=0.032).ConclusionThe existence of copathology significantly prolongs survival in patients with rapidly progressive dementia due to CJD. The study of major neurodegenerative-associated proteins in brains with CJD could allow us to further understand the molecular mechanisms behind prion diseases.
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Ravanidis, Stylianos, Fedon-Giasin Kattan et Epaminondas Doxakis. « Unraveling the Pathways to Neuronal Homeostasis and Disease : Mechanistic Insights into the Role of RNA-Binding Proteins and Associated Factors ». International Journal of Molecular Sciences 19, no 8 (3 août 2018) : 2280. http://dx.doi.org/10.3390/ijms19082280.
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The timing, dosage and location of gene expression are fundamental determinants of brain architectural complexity. In neurons, this is, primarily, achieved by specific sets of trans-acting RNA-binding proteins (RBPs) and their associated factors that bind to specific cis elements throughout the RNA sequence to regulate splicing, polyadenylation, stability, transport and localized translation at both axons and dendrites. Not surprisingly, misregulation of RBP expression or disruption of its function due to mutations or sequestration into nuclear or cytoplasmic inclusions have been linked to the pathogenesis of several neuropsychiatric and neurodegenerative disorders such as fragile-X syndrome, autism spectrum disorders, spinal muscular atrophy, amyotrophic lateral sclerosis and frontotemporal dementia. This review discusses the roles of Pumilio, Staufen, IGF2BP, FMRP, Sam68, CPEB, NOVA, ELAVL, SMN, TDP43, FUS, TAF15, and TIA1/TIAR in RNA metabolism by analyzing their specific molecular and cellular function, the neurological symptoms associated with their perturbation, and their axodendritic transport/localization along with their target mRNAs as part of larger macromolecular complexes termed ribonucleoprotein (RNP) granules.
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Lokireddy, Sudarsanareddy, Nikolay Vadimovich Kukushkin et Alfred Lewis Goldberg. « cAMP-induced phosphorylation of 26S proteasomes on Rpn6/PSMD11 enhances their activity and the degradation of misfolded proteins ». Proceedings of the National Academy of Sciences 112, no 52 (15 décembre 2015) : E7176—E7185. http://dx.doi.org/10.1073/pnas.1522332112.
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Although rates of protein degradation by the ubiquitin-proteasome pathway (UPS) are determined by their rates of ubiquitination, we show here that the proteasome’s capacity to degrade ubiquitinated proteins is also tightly regulated. We studied the effects of cAMP-dependent protein kinase (PKA) on proteolysis by the UPS in several mammalian cell lines. Various agents that raise intracellular cAMP and activate PKA (activators of adenylate cyclase or inhibitors of phosphodiesterase 4) promoted degradation of short-lived (but not long-lived) cell proteins generally, model UPS substrates having different degrons, and aggregation-prone proteins associated with major neurodegenerative diseases, including mutant FUS (Fused in sarcoma), SOD1 (superoxide dismutase 1), TDP43 (TAR DNA-binding protein 43), and tau. 26S proteasomes purified from these treated cells or from control cells and treated with PKA degraded ubiquitinated proteins, small peptides, and ATP more rapidly than controls, but not when treated with protein phosphatase. Raising cAMP levels also increased amounts of doubly capped 26S proteasomes. Activated PKA phosphorylates the 19S subunit, Rpn6/PSMD11 (regulatory particle non-ATPase 6/proteasome subunit D11) at Ser14. Overexpression of a phosphomimetic Rpn6 mutant activated proteasomes similarly, whereas a nonphosphorylatable mutant decreased activity. Thus, proteasome function and protein degradation are regulated by cAMP through PKA and Rpn6, and activation of proteasomes by this mechanism may be useful in treating proteotoxic diseases.
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Sharkey, Lisa M., Nathaniel Safren, Amit S. Pithadia, Julia E. Gerson, Mark Dulchavsky, Svetlana Fischer, Ronak Patel et al. « Mutant UBQLN2 promotes toxicity by modulating intrinsic self-assembly ». Proceedings of the National Academy of Sciences 115, no 44 (17 octobre 2018) : E10495—E10504. http://dx.doi.org/10.1073/pnas.1810522115.
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UBQLN2 is one of a family of proteins implicated in ubiquitin-dependent protein quality control and integrally tied to human neurodegenerative disease. Whereas wild-type UBQLN2 accumulates in intraneuronal deposits in several common age-related neurodegenerative diseases, mutations in the gene encoding this protein result in X-linked amyotrophic lateral sclerosis/frontotemporal dementia associated with TDP43 accumulation. Using in vitro protein analysis, longitudinal fluorescence imaging and cellular, neuronal, and transgenic mouse models, we establish that UBQLN2 is intrinsically prone to self-assemble into higher-order complexes, including liquid-like droplets and amyloid aggregates. UBQLN2 self-assembly and solubility are reciprocally modulated by the protein’s ubiquitin-like and ubiquitin-associated domains. Moreover, a pathogenic UBQLN2 missense mutation impairs droplet dynamics and favors amyloid-like aggregation associated with neurotoxicity. These data emphasize the critical link between UBQLN2’s role in ubiquitin-dependent pathways and its propensity to self-assemble and aggregate in neurodegenerative diseases.
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Lee, Saebom, Hye Guk Ryu, Sin Ho Kweon, Hyerynn Kim, Hyeonwoo Park, Kyung-Ha Lee, Sang-Min Jang, Chan Hyun Na, Sangjune Kim et Han Seok Ko. « c-Abl Regulates the Pathological Deposition of TDP-43 via Tyrosine 43 Phosphorylation ». Cells 11, no 24 (8 décembre 2022) : 3972. http://dx.doi.org/10.3390/cells11243972.
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Non-receptor tyrosine kinase, c-Abl plays a role in the pathogenesis of several neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease. Here, we found that TDP-43, which was one of the main proteins comprising pathological deposits in amyotrophic lateral sclerosis (ALS), is a novel substrate for c-Abl. The phosphorylation of tyrosine 43 of TDP-43 by c-Abl led to increased TDP-43 levels in the cytoplasm and increased the formation of G3BP1-positive stress granules in SH-SY5Y cells. The kinase-dead mutant of c-Abl had no effect on the cytoplasmic localization of TDP-43. The expression of phosphor-mimetic mutant Y43E of TDP-43 in primary cortical neurons accumulated the neurite granule. Furthermore, the phosphorylation of TDP-43 at tyrosine 43 by c-Abl promoted the aggregation of TDP-43 and increased neuronal cell death in primary cortical neurons, but not in c-Abl–deficient primary cortical neurons. Identification of c-Abl as the kinase of TDP43 provides new insight into the pathogenesis of ALS.
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Pal, Arun, Benedikt Kretner, Masin Abo-Rady, Hannes Glaβ, Banaja P. Dash, Marcel Naumann, Julia Japtok et al. « Concomitant gain and loss of function pathomechanisms in C9ORF72 amyotrophic lateral sclerosis ». Life Science Alliance 4, no 4 (22 février 2021) : e202000764. http://dx.doi.org/10.26508/lsa.202000764.
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Intronic hexanucleotide repeat expansions (HREs) in C9ORF72 are the most frequent genetic cause of amyotrophic lateral sclerosis, a devastating, incurable motoneuron (MN) disease. The mechanism by which HREs trigger pathogenesis remains elusive. The discovery of repeat-associated non-ATG (RAN) translation of dipeptide repeat proteins (DPRs) from HREs along with reduced exonic C9ORF72 expression suggests gain of toxic functions (GOFs) through DPRs versus loss of C9ORF72 functions (LOFs). Through multiparametric high-content (HC) live profiling in spinal MNs from induced pluripotent stem cells and comparison to mutant FUS and TDP43, we show that HRE C9ORF72 caused a distinct, later spatiotemporal appearance of mainly proximal axonal organelle motility deficits concomitant to augmented DNA double-strand breaks (DSBs), RNA foci, DPRs, and apoptosis. We show that both GOFs and LOFs were necessary to yield the overall C9ORF72 pathology. Increased RNA foci and DPRs concurred with onset of axon trafficking defects, DSBs, and cell death, although DSB induction itself did not phenocopy C9ORF72 mutants. Interestingly, the majority of LOF-specific DEGs were shared with HRE-mediated GOF DEGs. Finally, C9ORF72 LOF was sufficient—albeit to a smaller extent—to induce premature distal axonal trafficking deficits and increased DSBs.
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Anakor, Ekene, Vanessa Milla, Owen Connolly, Cecile Martinat, Pierre Francois Pradat, Julie Dumonceaux, William Duddy et Stephanie Duguez. « The Neurotoxicity of Vesicles Secreted by ALS Patient Myotubes Is Specific to Exosome-Like and Not Larger Subtypes ». Cells 11, no 5 (1 mars 2022) : 845. http://dx.doi.org/10.3390/cells11050845.
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Extracellular vesicles can mediate communication between tissues, affecting the physiological conditions of recipient cells. They are increasingly investigated in Amyotrophic Lateral Sclerosis, the most common form of Motor Neurone Disease, as transporters of misfolded proteins including SOD1, FUS, TDP43, or other neurotoxic elements, such as the dipeptide repeats resulting from C9orf72 expansions. EVs are classified based on their biogenesis and size and can be separated by differential centrifugation. They include exosomes, released by the fusion of multivesicular bodies with the plasma membrane, and ectosomes, also known as microvesicles or microparticles, resulting from budding or pinching of the plasma membrane. In the current study, EVs were obtained from the myotube cell culture medium of ALS patients or healthy controls. EVs of two different sizes, separating at 20,000 or 100,000 g, were then compared in terms of their effects on recipient motor neurons, astrocytes, and myotubes. Compared to untreated cells, the smaller, exosome-like vesicles of ALS patients reduced the survival of motor neurons by 31% and of myotubes by 18%, decreased neurite length and branching, and increased the proportion of stellate astrocytes, whereas neither those of healthy subjects, nor larger EVs of ALS or healthy subjects, had such effects.
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Ikenaka, Kensuke, Shinsuke Ishigaki, Yohei Iguchi, Kaori Kawai, Yusuke Fujioka, Satoshi Yokoi, Rehab F. Abdelhamid et al. « Characteristic Features of FUS Inclusions in Spinal Motor Neurons of Sporadic Amyotrophic Lateral Sclerosis ». Journal of Neuropathology & ; Experimental Neurology 79, no 4 (23 mars 2020) : 370–77. http://dx.doi.org/10.1093/jnen/nlaa003.
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Abstract Alterations of RNA metabolism caused by mutations in RNA-binding protein genes, such as transactivating DNA-binding protein-43 (TDP-43) and fused in sarcoma (FUS), have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Unlike the accumulation of TDP43, which is accepted as a pathological hall mark of sporadic ALS (sALS), FUS pathology in sALS is still under debate. Although immunoreactive inclusions of FUS have been detected in sALS patients previously, the technical limitation of signal detection, including the necessity of specific antigen retrieval, restricts our understanding of FUS-associated ALS pathology. In this study, we applied a novel detection method using a conventional antigen retrieval technique with Sudan Black B treatment to identify FUS-positive inclusions in sALS patients. We classified pathological motor neurons into 5 different categories according to the different aggregation characteristics of FUS and TDP-43. Although the granular type was more dominant for inclusions with TDP-43, the skein-like type was more often observed in FUS-positive inclusions, suggesting that these 2 proteins undergo independent aggregation processes. Moreover, neurons harboring FUS-positive inclusions demonstrated substantially reduced expression levels of dynactin-1, a retrograde motor protein, indicating that perturbation of nucleocytoplasmic transport is associated with the formation of cytoplasmic inclusions of FUS in sALS.
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Zhao, Yang, Fulei Tang, Daehoon Lee et Wen-Cheng Xiong. « Expression of Low Level of VPS35-mCherry Fusion Protein Diminishes Vps35 Depletion Induced Neuron Terminal Differentiation Deficits and Neurodegenerative Pathology, and Prevents Neonatal Death ». International Journal of Molecular Sciences 22, no 16 (4 août 2021) : 8394. http://dx.doi.org/10.3390/ijms22168394.
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Vps35 (vacuolar protein sorting 35) is a key component of retromer that consists of Vps35, Vps26, and Vps29 trimers, and sortin nexin dimers. Dysfunctional Vps35/retromer is believed to be a risk factor for development of various neurodegenerative diseases. Vps35Neurod6 mice, which selectively knock out Vps35 in Neurod6-Cre+ pyramidal neurons, exhibit age-dependent impairments in terminal differentiation of dendrites and axons of cortical and hippocampal neurons, neuro-degenerative pathology (i.e., increases in P62 and Tdp43 (TAR DNA-binding protein 43) proteins, cell death, and reactive gliosis), and neonatal death. The relationships among these phenotypes and the underlying mechanisms remain largely unclear. Here, we provide evidence that expression of low level of VPS35-mCherry fusion protein in Vps35Neurod6 mice could diminish the phenotypes in an age-dependent manner. Specifically, we have generated a conditional transgenic mouse line, LSL-Vps35-mCherry, which expresses VPS35-mCherry fusion protein in a Cre-dependent manner. Crossing LSL-Vps35-mCherry with Vps35Neurod6 to obtain TgVPS35-mCherry, Vps35Neurod6 mice prevent the neonatal death and diminish the dendritic morphogenesis deficit and gliosis at the neonatal, but not the adult age. Further studies revealed that the Vps35-mCherry transgene expression was low, and the level of Vps35 mRNA comprised only ~5–7% of the Vps35 mRNA of control mice. Such low level of VPS35-mCherry could restore the amount of other retromer components (Vps26a and Vps29) at the neonatal age (P14). Importantly, the neurodegenerative pathology presented in the survived adult TgVps35-mCherry; Vps35Neurod6 mice. These results demonstrate the sufficiency of low level of VPS35-mCherry fusion protein to diminish the phenotypes in Vps35Neurod6 mice at the neonatal age, verifying a key role of neuronal Vps35 in stabilizing retromer complex proteins, and supporting the view for Vps35 as a potential therapeutic target for neurodegenerative diseases.
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Schmidt, Hermann Broder, Ariana Barreau et Rajat Rohatgi. « Phase separation-deficient TDP43 remains functional in splicing ». Nature Communications 10, no 1 (25 octobre 2019). http://dx.doi.org/10.1038/s41467-019-12740-2.
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Abstract Intrinsically disordered regions (IDRs) are often fast-evolving protein domains of low sequence complexity that can drive phase transitions and are commonly found in many proteins associated with neurodegenerative diseases, including the RNA processing factor TDP43. Yet, how phase separation contributes to the physiological functions of TDP43 in cells remains enigmatic. Here, we combine systematic mutagenesis guided by evolutionary sequence analysis with a live-cell reporter assay of TDP43 phase dynamics to identify regularly-spaced hydrophobic motifs separated by flexible, hydrophilic segments in the IDR as a key determinant of TDP43 phase properties. This heuristic framework allows customization of the material properties of TDP43 condensates to determine effects on splicing function. Remarkably, even a mutant that fails to phase-separate at physiological concentrations can still efficiently mediate the splicing of a quantitative, single-cell splicing reporter and endogenous targets. This suggests that the ability of TDP43 to phase-separate is not essential for its splicing function.
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Zhou, Dongheng, Huanhuan Yan, Shuying Yang, Yuhong Zhang, Xiaoyan Xu, Xufeng Cen, Kai Lei et Hongguang Xia. « SC75741, A Novel c-Abl Inhibitor, Promotes the Clearance of TDP25 Aggregates via ATG5-Dependent Autophagy Pathway ». Frontiers in Pharmacology 12 (29 octobre 2021). http://dx.doi.org/10.3389/fphar.2021.741219.
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Abnormal accumulation of TDP43-related mutant proteins in the cytoplasm causes amyotrophic lateral sclerosis (ALS). Herein, unbiased drug screening approaches showed that SC75741, a multi-target inhibitor, inhibited inflammation-induced aggregation by inhibiting NF-κB and also degraded already aggregated proteins by inhibiting c-Abl mediated autophagy-lysosomal pathway. We delineate the mechanism that SC75741 could markedly enhance TFEB nuclear translocation by an mTORC1-independent TFEB regulatory pathway. In addition, SC75741 enhanced the interaction between p62 with TDP25 and LC3C, thus promoting TDP25 degradation. Taken together, these findings show that SC75741 has beneficial neuroprotective effects in ALS. Our study elucidates that dual-targeted inhibition of c-Abl and NF-κB may be a potential treatment for TDP43 proteinopathies and ALS.
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Jiang, Tianlin, Yanli Wang, Xiaohong Wang et Jun Xu. « CHCHD2 and CHCHD10 : Future therapeutic targets in cognitive disorder and motor neuron disorder ». Frontiers in Neuroscience 16 (18 août 2022). http://dx.doi.org/10.3389/fnins.2022.988265.
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CHCHD2 and CHCHD10 are homolog mitochondrial proteins that play key roles in the neurological, cardiovascular, and reproductive systems. They are also involved in the mitochondrial metabolic process. Although previous research has concentrated on their functions within mitochondria, their functions within apoptosis, synaptic plasticity, cell migration as well as lipid metabolism remain to be concluded. The review highlights the different roles played by CHCHD2 and/or CHCHD10 binding to various target proteins (such as OPA-1, OMA-1, PINK, and TDP43) and reveals their non-negligible effects in cognitive impairments and motor neuron diseases. This review focuses on the functions of CHCHD2 and/or CHCHD10. This review reveals protective effects and mechanisms of CHCHD2 and CHCHD10 in neurodegenerative diseases characterized by cognitive and motor deficits, such as frontotemporal dementia (FTD), Lewy body dementia (LBD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS). However, there are numerous specific mechanisms that have yet to be elucidated, and additional research into these mechanisms is required.
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Portelli, Stephanie, Amanda Albanaz, Douglas Eduardo Valente Pires et David Benjamin Ascher. « Identifying the molecular drivers of ALS-implicated missense mutations ». Journal of Medical Genetics, 30 septembre 2022, jmg—2022–108798. http://dx.doi.org/10.1136/jmg-2022-108798.
Texte intégralRésumé :
BackgroundAmyotrophic lateral sclerosis (ALS) is a progressively fatal, neurodegenerative disease associated with both motor and non-motor symptoms, including frontotemporal dementia. Approximately 10% of cases are genetically inherited (familial ALS), while the majority are sporadic. Mutations across a wide range of genes have been associated; however, the underlying molecular effects of these mutations and their relation to phenotypes remain poorly explored.MethodsWe initially curated an extensive list (n=1343) of missense mutations identified in the clinical literature, which spanned across 111 unique genes. Of these, mutations in genes SOD1, FUS and TDP43 were analysed using in silico biophysical tools, which characterised changes in protein stability, interactions, localisation and function. The effects of pathogenic and non-pathogenic mutations within these genes were statistically compared to highlight underlying molecular drivers.ResultsCompared with previous ALS-dedicated databases, we have curated the most extensive missense mutation database to date and observed a twofold increase in unique implicated genes, and almost a threefold increase in the number of mutations. Our gene-specific analysis identified distinct molecular drivers across the different proteins, where SOD1 mutations primarily reduced protein stability and dimer formation, and those in FUS and TDP-43 were present within disordered regions, suggesting different mechanisms of aggregate formation.ConclusionUsing our three genes as case studies, we identified distinct insights which can drive further research to better understand ALS. The information curated in our database can serve as a resource for similar gene-specific analyses, further improving the current understanding of disease, crucial for the development of treatment strategies.
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Trist, Benjamin G., Jennifer A. Fifita, Alison Hogan, Natalie Grima, Bradley Smith, Claire Troakes, Caroline Vance et al. « Co-deposition of SOD1, TDP-43 and p62 proteinopathies in ALS : evidence for multifaceted pathways underlying neurodegeneration ». Acta Neuropathologica Communications 10, no 1 (25 août 2022). http://dx.doi.org/10.1186/s40478-022-01421-9.
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AbstractMultiple neurotoxic proteinopathies co-exist within vulnerable neuronal populations in all major neurodegenerative diseases. Interactions between these pathologies may modulate disease progression, suggesting they may constitute targets for disease-modifying treatments aiming to slow or halt neurodegeneration. Pairwise interactions between superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP-43) and ubiquitin-binding protein 62/sequestosome 1 (p62) proteinopathies have been reported in multiple transgenic cellular and animal models of amyotrophic lateral sclerosis (ALS), however corresponding examination of these relationships in patient tissues is lacking. Further, the coalescence of all three proteinopathies has not been studied in vitro or in vivo to date. These data are essential to guide therapeutic development and enhance the translation of relevant therapies into the clinic. Our group recently profiled SOD1 proteinopathy in post-mortem spinal cord tissues from familial and sporadic ALS cases, demonstrating an abundance of structurally-disordered (dis)SOD1 conformers which become mislocalized within these vulnerable neurons compared with those of aged controls. To explore any relationships between this, and other, ALS-linked proteinopathies, we profiled TDP-43 and p62 within spinal cord motor neurons of the same post-mortem tissue cohort using multiplexed immunofluorescence and immunohistochemistry. We identified distinct patterns of SOD1, TDP43 and p62 co-deposition and subcellular mislocalization between motor neurons of familial and sporadic ALS cases, which we primarily attribute to SOD1 gene status. Our data demonstrate co-deposition of p62 with mutant and wild-type disSOD1 and phosphorylated TDP-43 in familial and sporadic ALS spinal cord motor neurons, consistent with attempts by p62 to mitigate SOD1 and TDP-43 deposition. Wild-type SOD1 and TDP-43 co-deposition was also frequently observed in ALS cases lacking SOD1 mutations. Finally, alterations to the subcellular localization of the three proteins were tightly correlated, suggesting close relationships between the regulatory mechanisms governing the subcellular compartmentalization of these proteins. Our study is the first to profile spatial relationships between SOD1, TDP-43 and p62 pathologies in post-mortem spinal cord motor neurons of ALS patients, previously only studied in vitro. Our findings suggest interactions between these three key ALS-linked proteins are likely to modulate the formation of their respective proteinopathies, and perhaps the rate of motor neuron degeneration, in ALS patients.