TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis

By J. Sreedharan, I. Blair, V. Tripathi, Xun Hu, C. Vance, B. Rogelj, S. Ackerley, Jennifer C Durnall, K. Williams, E. Buratti and 8 more. Science, 2008

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Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder characterized pathologically by ubiquitinated TAR DNA binding protein (TDP-43) inclusions. The function of TDP-43 in the nervous system is uncertain, and a mechanistic role in neurodegeneration remains speculative. We identified neighboring mutations in a highly conserved region of TARDBP in sporadic and familial ALS cases. TARDBPM337V segregated with disease within one kindred and a genome-wide scan confirmed that linkage was restricted to chromosome 1p36, which contains the TARDBP locus. Mutant forms of TDP-43 fragmented in vitro more readily than wild type and, in vivo, caused neural apoptosis and developmental delay in the chick embryo. Our evidence suggests a pathophysiological link between TDP-43 and ALS.

Subfields: Genetics, Molecular Biology, Neurology

View Paper: https://www.semanticscholar.org/paper/a097e30f6c040511bb59771239e7a66d03895d9f

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Citations in the corpus

Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023, background): “303,304 Mutations in the SOD1 gene (encoding superoxide dismutase 1) occur in ~20% of cases, 305 while mutations in TARDBP (encoding TAR DNA-binding protein 43 [TDP43]) 306 and FUS (encoding the fused in sarcoma protein) have a lower frequency ( 5%).”
Expanded GGGGCC hexanucleotide repeat in non-coding region of C9ORF72 causes chromosome 9p-linked frontotemporal dementia and amyotrophic lateral sclerosis (2011, positive): “The loss of variant 1 expression in the GGGGCC repeat carriers was further confirmed by real-time RT-PCR using a custom-designed Taqman ALS = amyotrophic lateral sclerosis; c9FTD/ALS = (GGGGCC) n repeat expansion at chromosome 9p identified in this study; FTD = frontotemporal dementia; FTLD-TDP = fr”
A census of human RNA-binding proteins (2014, background): “TARDBP amyotrophic lateral sclerosis (ALS) missense mutation leading to protein aggregation (Sreedharan et al., 2008)”
TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration. (2010, background): “Expression of human TDP-43 carrying disease-associated mutations was suggested to exhibit higher toxicity than the wild-type protein in chick embryos (14) and primary rodent neurons (223,227).”
13 reasons why the brain is susceptible to oxidative stress (2018, background): “TD43—a pathological trigger in ALS and frontotemporal dementia [53]—reduces MAM contacts and thereby disrupts Ca homeostasis.”
Tar DNA Binding Protein-43 (TDP-43) Associates with Stress Granules: Analysis of Cultured Cells and Pathological Brain Tissue (2010, background): “Previous studies suggest that Q331K TDP-43 expression causes cell death [2].”
ALS‐associated fused in sarcoma (FUS) mutations disrupt Transportin‐mediated nuclear import (2010, background): “Of these, about 5–10% are caused by mutations in the TAR DNA-binding protein 43 (TDP-43) gene on chromosome 1 (Gitcho et al, 2008; Kabashi et al, 2008; Mackenzie and Rademakers, 2008; Sreedharan et al, 2008) or the FUS gene on chromosome 16 (Kwiatkowski et al, 2009; Vance et al, 2009).”
TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS (2020, background): “, A315T, Q331K, or M337V) have been found to cause ALS (Kabashi et al., 2008; Sreedharan et al., 2008).”
Autophagy and apoptosis dysfunction in neurodegenerative disorders. (2014, positive): “Mutant forms of the protein TDP-43 encoded by the TARDBP gene (Sreedharan et al., 2008), as well as mutations in the FUS gene encoding an RNA binding protein (Vance et al., 2009), are also among the genes associated with familial ALS (Martin, 2011).”
Oxidative stress in ALS: key role in motor neuron injury and therapeutic target. (2010, background): “pathogenesis of ALS, with the discovery of mutations in two genes with RNA/DNA-binding functions, TDP-43 [11,12] and FUS/TLS [9,10],”
Exome sequencing reveals VCP mutations as a cause of familial ALS (2010, positive): “Mutations of ANG, DCTN1, FUS, OPTN, SETX, SOD1, and TDP-43 were similarly excluded in cases carrying VCP mutations.”