Journal
NEURON
Volume 95, Issue 4, Pages 808-+Publisher
CELL PRESS
DOI: 10.1016/j.neuron.2017.07.025
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Funding
- Mayo Clinic for Individualized Medicine
- Arizona Alzheimer's Consortium
- Howard Hughes Medical Institute [045104-Taylor]
- Clinical Research in ALS and related disorders for Therapeutic Development (CReATe) Consortium [1U54NS092091]
- Canadian Institutes for Health Research [74580]
- NIH [R35NS097974, R35NS097261, R35NS097273, P50AG016574, P50NS072187, P01NS084974, U01AG006576, U54NS092091, P30AG019610, R01AG031581, R01NS072248, R01NS075764]
- Canadian Consortium on Neurodegeneration in Aging [137794]
- ALS Canada-Brain Canada Hudson Grant
- Richard C. Kendall Fellowship
- Younkin Fellowship
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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are age-related neurodegenerative disorders with shared genetic etiologies and overlapping clinical and pathological features. Here we studied a novel ALS/FTD family and identified the P362L mutation in the low-complexity domain (LCD) of T cell-restricted intracellular antigen-1 (TIA1). Subsequent genetic association analyses showed an increased burden of TIA1 LCD mutations in ALS patients compared to controls (p = 8.7 x 10(-6)). Postmortem neuropathology of five TIA1 mutations carriers showed a consistent pathological signature with numerous round, hyaline, TAR DNA-binding protein 43 (TDP-43)-positive inclusions. TIA1 mutations significantly increased the propensity of TIA1 protein to under-gophase transition. Inlive cells, TIA1 mutations delayed stress granule (SG) disassembly and promoted the accumulation of non-dynamic SGs that harbored TDP-43. Moreover, TDP-43 in SGs became less mobile and insoluble. The identification of TIA1 mutations in ALS/FTD reinforces the importance of RNA metabolism and SG dynamics in ALS/FTD pathogenesis.
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