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Journal ArticleDOI: 10.1038/S41583-021-00431-1

Triad of TDP43 control in neurodegeneration: autoregulation, localization and aggregation.

02 Mar 2021-Nature Reviews Neuroscience (Springer Science and Business Media LLC)-Vol. 22, Iss: 4, pp 197-208
Abstract: Cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP43; also known as TARDBP or TDP-43) is a key pathological feature of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP43 typically resides in the nucleus but can shuttle between the nucleus and the cytoplasm to exert its multiple functions, which include regulation of the splicing, trafficking and stabilization of RNA. Cytoplasmic mislocalization and nuclear loss of TDP43 have both been associated with ALS and FTD, suggesting that calibrated levels and correct localization of TDP43 — achieved through an autoregulatory loop and tightly controlled nucleocytoplasmic transport — safeguard its normal function. Furthermore, TDP43 can undergo phase transitions, including its dispersion into liquid droplets and its accumulation into irreversible cytoplasmic aggregates. Thus, autoregulation, nucleocytoplasmic transport and phase transition are all part of an intrinsic control system regulating the physiological levels and localization of TDP43, and together are essential for the cellular homeostasis that is affected in neurodegenerative disease. Accumulation of TAR DNA-binding protein 43 (TDP43) in the neuronal cytoplasm and its loss from the nucleus are characteristic features of several neurodegenerative diseases. Tziortzouda, Van Den Bosch and Hirth describe three intrinsic mechanisms that control TDP43 levels and localization and are altered to drive pathology.

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Topics: Neurodegeneration (55%), Nucleocytoplasmic Transport (54%), TARDBP (53%) ... read more
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20 results found


Open accessJournal ArticleDOI: 10.3390/IJMS22116016
Abstract: Intrinsic disorder is a natural feature of polypeptide chains, resulting in the lack of a defined three-dimensional structure. Conformational changes in intrinsically disordered regions of a protein lead to unstable β-sheet enriched intermediates, which are stabilized by intermolecular interactions with other β-sheet enriched molecules, producing stable proteinaceous aggregates. Upon misfolding, several pathways may be undertaken depending on the composition of the amino acidic string and the surrounding environment, leading to different structures. Accumulating evidence is suggesting that the conformational state of a protein may initiate signalling pathways involved both in pathology and physiology. In this review, we will summarize the heterogeneity of structures that are produced from intrinsically disordered protein domains and highlight the routes that lead to the formation of physiological liquid droplets as well as pathogenic aggregates. The most common proteins found in aggregates in neurodegenerative diseases and their structural variability will be addressed. We will further evaluate the clinical relevance and future applications of the study of the structural heterogeneity of protein aggregates, which may aid the understanding of the phenotypic diversity observed in neurodegenerative disorders.

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Topics: Protein aggregation (52%)

5 Citations


Open accessJournal ArticleDOI: 10.1016/J.CELL.2021.07.018
02 Sep 2021-Cell
Abstract: Summary Mutations causing amyotrophic lateral sclerosis (ALS) often affect the condensation properties of RNA-binding proteins (RBPs). However, the role of RBP condensation in the specificity and function of protein-RNA complexes remains unclear. We created a series of TDP-43 C-terminal domain (CTD) variants that exhibited a gradient of low to high condensation propensity, as observed in vitro and by nuclear mobility and foci formation. Notably, a capacity for condensation was required for efficient TDP-43 assembly on subsets of RNA-binding regions, which contain unusually long clusters of motifs of characteristic types and density. These "binding-region condensates" are promoted by homomeric CTD-driven interactions and required for efficient regulation of a subset of bound transcripts, including autoregulation of TDP-43 mRNA. We establish that RBP condensation can occur in a binding-region-specific manner to selectively modulate transcriptome-wide RNA regulation, which has implications for remodeling RNA networks in the context of signaling, disease, and evolution.

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Topics: RNA-binding protein (58%), RNA (53%), ICLIP (51%)

3 Citations


Open accessPosted ContentDOI: 10.1101/2021.04.30.442163
da Silva Lg1, Simonetti F1, Simonetti F2, Hutten S1  +11 moreInstitutions (5)
30 Apr 2021-bioRxiv
Abstract: Post-translational modifications (PTMs) have emerged as key modulators of protein phase separation and have been linked to protein aggregation in neurodegenerative disorders. The major aggregating protein in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), the RNA-binding protein TDP-43, is hyperphosphorylated in disease on several C-terminal serine residues, which is generally believed to promote TDP-43 aggregation. Here, we show that hyperphosphorylation by Casein kinase 1δ or C-terminal phosphomimetic mutations surprisingly reduce TDP-43 phase separation and aggregation and render TDP-43 condensates more liquid-like and dynamic. Multi-scale simulations reveal reduced homotypic interactions of TDP-43 low complexity domains through enhanced solvation of phosphomimetic residues. Cellular experiments show that phosphomimetic substitutions do not affect nuclear import or RNA regulatory functions of TDP-43, but suppress accumulation of TDP-43 in membrane-less organelles and promote its solubility in neurons. We propose that TDP-43 hyperphosphorylation may be a protective cellular response to counteract TDP-43 aggregation.

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3 Citations



Open accessJournal ArticleDOI: 10.3390/IJMS22083985
Abstract: A common pathological hallmark of several neurodegenerative diseases, including amyotrophic lateral sclerosis, is cytoplasmic mislocalization and aggregation of nuclear RNA-binding protein TDP-43. Perry disease, which displays inherited atypical parkinsonism, is a type of TDP-43 proteinopathy. The causative gene DCTN1 encodes the largest subunit of the dynactin complex. Dynactin associates with the microtubule-based motor cytoplasmic dynein and is required for dynein-mediated long-distance retrograde transport. Perry disease-linked missense mutations (e.g., p.G71A) reside within the CAP-Gly domain and impair the microtubule-binding abilities of DCTN1. However, molecular mechanisms by which such DCTN1 mutations cause TDP-43 proteinopathy remain unclear. We found that DCTN1 bound to TDP-43. Biochemical analysis using a panel of truncated mutants revealed that the DCTN1 CAP-Gly-basic supradomain, dynactin domain, and C-terminal region interacted with TDP-43, preferentially through its C-terminal region. Remarkably, the p.G71A mutation affected the TDP-43-interacting ability of DCTN1. Overexpression of DCTN1G71A, the dynactin-domain fragment, or C-terminal fragment, but not the CAP-Gly-basic fragment, induced cytoplasmic mislocalization and aggregation of TDP-43, suggesting functional modularity among TDP-43-interacting domains of DCTN1. We thus identified DCTN1 as a new player in TDP-43 cytoplasmic-nuclear transport, and showed that dysregulation of DCTN1-TDP-43 interactions triggers mislocalization and aggregation of TDP-43, thus providing insights into the pathological mechanisms of Perry disease and other TDP-43 proteinopathies.

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Topics: DCTN1 (61%), Dynactin (60%)

2 Citations


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200 results found


Journal ArticleDOI: 10.1126/SCIENCE.1134108
Manuela Neumann1, Deepak M. Sampathu1, Linda K. Kwong1, Adam C. Truax1  +15 moreInstitutions (5)
06 Oct 2006-Science
Abstract: Ubiquitin-positive, tau- and alpha-synuclein-negative inclusions are hallmarks of frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis. Although the identity of the ubiquitinated protein specific to either disorder was unknown, we showed that TDP-43 is the major disease protein in both disorders. Pathologic TDP-43 was hyper-phosphorylated, ubiquitinated, and cleaved to generate C-terminal fragments and was recovered only from affected central nervous system regions, including hippocampus, neocortex, and spinal cord. TDP-43 represents the common pathologic substrate linking these neurodegenerative disorders.

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Topics: TARDBP (65%), Frontotemporal lobar degeneration (65%), Frontotemporal dementia (58%) ... read more

4,754 Citations


Open accessJournal ArticleDOI: 10.1016/J.NEURON.2011.09.011
20 Oct 2011-Neuron
Abstract: Several families have been reported with autosomal-dominant frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), genetically linked to chromosome 9p21. Here, we report an expansion of a noncoding GGGGCC hexanucleotide repeat in the gene C9ORF72 that is strongly associated with disease in a large FTD/ALS kindred, previously reported to be conclusively linked to chromosome 9p. This same repeat expansion was identified in the majority of our families with a combined FTD/ALS phenotype and TDP-43-based pathology. Analysis of extended clinical series found the C9ORF72 repeat expansion to be the most common genetic abnormality in both familial FTD (11.7%) and familial ALS (23.5%). The repeat expansion leads to the loss of one alternatively spliced C9ORF72 transcript and to formation of nuclear RNA foci, suggesting multiple disease mechanisms. Our findings indicate that repeat expansion in C9ORF72 is a major cause of both FTD and ALS.

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Topics: Trinucleotide repeat expansion (58%), C9orf72 Protein (58%), DNA Repeat Expansion (56%) ... read more

3,580 Citations


Open accessJournal ArticleDOI: 10.1016/J.NEURON.2011.09.010
20 Oct 2011-Neuron
Abstract: The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases. We have previously shown that a founder haplotype, covering the MOBKL2b, IFNK, and C9ORF72 genes, is present in the majority of cases linked to this region. Here we show that there is a large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 on the affected haplotype. This repeat expansion segregates perfectly with disease in the Finnish population, underlying 46.0% of familial ALS and 21.1% of sporadic ALS in that population. Taken together with the D90A SOD1 mutation, 87% of familial ALS in Finland is now explained by a simple monogenic cause. The repeat expansion is also present in one-third of familial ALS cases of outbred European descent, making it the most common genetic cause of these fatal neurodegenerative diseases identified to date.

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Topics: Trinucleotide repeat expansion (58%), C9orf72 Protein (55%), DNA Repeat Expansion (54%) ... read more

3,304 Citations


Journal ArticleDOI: 10.1016/0896-6273(89)90210-9
01 Oct 1989-Neuron
Abstract: We have determined the sequences of isoforms of human tau protein, which differ from previously reported forms by insertions of 29 or 58 amino acids in the amino-terminal region. Complementary DNA cloning shows that the insertions occur in combination with both three and four tandem repeats. RNAase protection assays indicate that transcripts encoding isoforms with the insertions are expressed in an adult-specific manner. Transcripts encoding four tandem repeats are also expressed in an adult-specific manner, whereas mRNAs encoding three tandem repeats are expressed throughout life, including in fetal brain. The levels of transcripts encoding the 29 or 58 amino acid inserts were not significantly changed in cerebral cortex from patients with Alzheimer's disease. Antisera raised against synthetic peptides corresponding to these different human tau isoforms demonstrate that multiple tau protein isoforms are incorporated into the neurofibrillary tangles of Alzheimer's disease.

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Topics: Tau protein (60%), Tandem repeat (59%), Gene isoform (52%) ... read more

2,049 Citations


Journal ArticleDOI: 10.1016/J.BBRC.2006.10.093
Abstract: Ubiquitin-positive tau-negative neuronal cytoplasmic inclusions and dystrophic neurites are common pathological features in frontotemporal lobar degeneration (FTLD) with or without symptoms of motor neuron disease and in amyotrophic lateral sclerosis (ALS). Using biochemical and immunohistochemical analyses, we have identified a TAR DNA-binding protein of 43 kDa (TDP-43), a nuclear factor that functions in regulating transcription and alternative splicing, as a component of these structures in FTLD. Furthermore, skein-like inclusions, neuronal intranuclear inclusions, and glial inclusions in the spinal cord of ALS patients are also positive for TDP-43. Dephosphorylation treatment of the sarkosyl insoluble fraction has shown that abnormal phosphorylation takes place in accumulated TDP-43. The common occurrence of intracellular accumulations of TDP-43 supports the hypothesis that these disorders represent a clinicopathological entity of a single disease, and suggests that they can be newly classified as a proteinopathy of TDP-43.

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Topics: Frontotemporal lobar degeneration (61%), TARDBP (60%), Amyotrophic lateral sclerosis (54%) ... read more

1,981 Citations


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202118
20202