TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis
Open accessAbstract
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.
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Mutations in TARDBP are the third most common cause of familial autosomal dominant ALS and account for rare cases of sporadic ALS.
“Mutations in TARDBP, which encodes the transactive response DNA binding protein 43 kDa (TDP-43), are the third most common cause of familial autosomal dominant ALS and account for rare cases of sporadic ALS [290–293].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [291]
Mutations in TARDBP and FUS have a lower frequency (<5%) in ALS.
“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%).307”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [306]
Microglia in the late stage accelerate disease progression.
“emphasizing that microglia in the late stage accelerate disease progression.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [306]
Mutations in TARDBP identified in patients with ALS or FTD indicate a mechanistic link between TDP-43 and ALS/FTD and suggest a common underlying mechanism.
“and mutations in TARDBP, the gene encoding TDP-43, have been identified in patients with ALS or FTD,306,333 indicating a mechanistic link between TDP-43 and ALS/FTD and also suggesting a common underlying mechanism”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [306]
Reduced mutant levels in microglia did not have much effect on early disease progression, but substantially slowed it later on.
“Reduced mutant levels in microglia did not have much effect on early disease progression, but substantially slowed it later on,306”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [306]
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Self-citation
- Authors
- Sreedharan, J., Blair, I. P., Tripathi, V. B., Hu, X., Vance, C., Rogelj, B., Ackerley, S., Durnall, J. C., Williams, K. L., Buratti, E., Baralle, F., de Belleroche, J., Mitchell, J. D., Leigh, P. N., Al-Chalabi, A., Miller, C. C., Nicholson, G., & Shaw, C. E.
- Affiliations
- The University of Sydney (AU)
- Department of Clinical Neuroscience, King's College London, Medical Research Council (MRC) Centre for Neurodegeneration Research, and Institute of Psychiatry, London, SE5 8AF, UK.
- Corresponding author
- Sreedharan, Jemeen
- Blair, Ian P.
- Tripathi, Vineeta B.
- Nicholson, Garth
- Shaw, Christopher E.
- ORCID
- Venue
- Science
- Published
- 2008-03-21
- Volume
- 319
- Issue
- 5870
- Pages
- 1668-1672
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC7116650
- OpenAlex
- W1619082318
- Cited by
- 2,630
- References
- 29
- Citations by year
- 2026: 73 · 2025: 88 · 2024: 104 · 2023: 141 · 2022: 149 · 2021: 141 · 2020: 149 · 2019: 121 · 2018: 147 · 2017: 117 · 2016: 156 · 2015: 154 · 2014: 167 · 2013: 168 · 2012: 192
- FWCI
- 119.36
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Figshare (submittedVersion, cc-by)
- Research Portal (King's College London) (submittedVersion)
- Sussex Research Online (University of Sussex) (submittedVersion)
- Funders
- Wellcome Trust (076671)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- amyotrophic lateral sclerosis, TDP-43, TARDBP, familial ALS, sporadic ALS, TDP-43 mutations, chromosome 1p36, genetic linkage, ubiquitinated inclusions, neurodegeneration, neuronal apoptosis, protein fragmentation
- MeSH terms
- Adult, Amino Acid Sequence, Amyotrophic Lateral Sclerosis, Animals, Chick Embryo, Chromosomes, Human, Pair 1, Cricetulus, DNA-Binding Proteins, Female, Cricetinae, Humans, Male, Middle Aged, Molecular Sequence Data, Neurons, CHO Cells, Apoptosis, Microsatellite Repeats, Amino Acid Substitution, Mutation, Missense, Embryonic Development, Mutant Proteins
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