TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis

Topic: Brain proteins, microglia and lab models

Background TDP-43 is a major component of the ubiquitinated inclusions that characterise amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with ubiquitin inclusions (FTLD-U). TDP-43 is an RNA-binding and DNA-binding protein that has many functions and is encoded by the TAR DNA-binding protein gene (TARDBP) on chromosome 1. Our aim was to investigate whether TARDBP is a candidate disease gene for familial ALS that is not associated with mutations in superoxide dismutase 1 (SOD1). Methods TARDBP was sequenced in 259 patients with ALS, FTLD, or both. We used TaqMan-based SNP genotyping to screen for the identified variants in control groups matched to two kindreds of patients for age and ethnic origin. Additional clinical, genetic, and pathological assessments were made in these two families. Findings We identified two variants in TARDBP, which would encode Gly290Ala and Gly298Ser forms of TDP-43, in two kindreds with familial ALS. The variants seem to be pathogenic because they co-segregated with disease in both families, were absent in controls, and were associated with TDP-43 neuropathology in both members of one of these families for whom CNS tissue was available. Interpretation The Gly290Ala and Gly298Ser mutations are located in the glycine-rich domain of TDP-43, which regulates gene expression and mediates protein-protein interactions such as those with heterogeneous ribonucleoproteins. Owing to the varied and important cellular functions of TDP-43, these mutations might cause neurodegeneration through both gains and losses of function. The finding of pathogenic mutations in TARDBP implicates TDP-43 as an active mediator of neurodegeneration in TDP-43 proteinopathies, a class of disorder that includes ALS and FTLD-U. Funding National Institutes of Health (AG10124, AG17586, AG005136-22, PO1 AG14382), Department of Veterans Affairs, Friedrich-Baur Stiftung (0017/2007), US Public Health Service, ALS Association, and Fundació 'la Caixa'.

Key findings

• Our aim was to investigate whether TARDBP is a candidate disease gene for familial ALS that is not associated with mutations in superoxide dismutase 1 (SOD1).
• The variants seem to be pathogenic because they co-segregated with disease in both families, were absent in controls, and were associated with TDP-43 neuropathology in both members of one of these families for whom CNS tissue was available.

Why it matters

Researchers sequenced the TARDBP gene in 259 people with ALS, frontotemporal lobar degeneration or both, and found two variants (Gly290Ala and Gly298Ser) in two families with inherited ALS. The authors judged the variants likely disease-causing because they tracked with illness in both families, were absent in matched controls, and came with TDP-43 brain pathology in the one family with tissue available. They suggest this makes TDP-43 an active driver of nerve-cell damage, not just a by-product. This is a study of ALS, not Alzheimer's disease, and it tests no treatment.

Study details

• Participants259
• Evidence strengthLow

Read the original

• DOI: 10.1016/s1474-4422(08)70071-1
• PubMed: 18396105
• Original source →
• Free full text: PubMed Central →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

@article{vandeerlin2008-18396105,
  author  = {Van Deerlin, V. M. and Leverenz, J. B. and Bekris, L. M. and Bird, T. D. and Yuan, W. and Elman, L. B. and Clay, D. and Wood, E. M. and others},
  title   = {{TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis}},
  journal = {The Lancet. Neurology},
  year    = {2008},
  doi     = {10.1016/s1474-4422(08)70071-1},
  pmid    = {18396105},
  url     = {https://doi.org/10.1016/s1474-4422(08)70071-1}
}

Studies this one cites

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• TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis Science · 2008-02-28 · usefulness score 64/100 · Disease mechanisms
• Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations Annals of neurology · 2007-05-01 · usefulness score 63/100 · Brain tissue and pathology
• Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Science (New York, N.Y.) · 2006-10-01 · usefulness score 62/100 · Lewy body dementia
• TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Biochemical and biophysical research communications · 2006-10-30 · usefulness score 56/100 · Lewy body dementia
• Are amyotrophic lateral sclerosis patients cognitively normal? Neurology · 2003-04-01 · usefulness score 54/100 · Getting a diagnosis

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