Journal article
TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics
Neuron (Cambridge, Mass.), v 95(4), pp 808-816
16 Aug 2017
PMID: 28817800
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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 × 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 undergo phase transition. In live 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.
•Mutations affecting the low-complexity domain of TIA1 cause ALS and ALS-FTD•ALS-linked TIA1 mutations share a neuropathological TDP-43 signature•TIA1 mutations promote phase separation and impair stress granule dynamics•TDP-43 recruited to poorly dynamic stress granules becomes immobile and insoluble
Mackenzie et al. report the identification of mutations in TIA1 as a novel cause of ALS and ALS-FTD. ALS-linked mutations perturb phase transitions of TIA1, which impair the dynamics of stress granules and indirectly promote TDP-43 insolubility.
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Details
- Title
- TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics
- Creators
- Ian R. Mackenzie - University of British ColumbiaAlexandra M. Nicholson - Mayo ClinicMohona Sarkar - St. Jude Children's Research HospitalJames Messing - Howard Hughes Medical InstituteMaria D. Purice - Howard Hughes Medical InstituteCyril Pottier - Mayo ClinicKavya Annu - St. Jude Children's Research HospitalMatt Baker - Mayo ClinicRalph B. Perkerson - Mayo ClinicAishe Kurti - Mayo ClinicBillie J. Matchett - Mayo ClinicTanja Mittag - St. Jude Children's Research HospitalJamshid Temirov - St. Jude Children's Research HospitalGing-Yuek R. Hsiung - University of British ColumbiaCharles Krieger - Simon Fraser UniversityMelissa E. Murray - Jacksonville CollegeMasato Kato - The University of Texas Southwestern Medical CenterJohn D. Fryer - Jacksonville CollegeLeonard Petrucelli - Jacksonville CollegeLorne Zinman - University of TorontoSandra Weintraub - Northwestern UniversityMarsel Mesulam - Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USAJulia Keith - University of TorontoSasha A. Zivkovic - University of PittsburghVeronica Hirsch-Reinshagen - University of British ColumbiaRaymond P. Roos - University of ChicagoStephan Züchner - Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA.Neill R. Graff-Radford - Jacksonville CollegeRonald C. Petersen - Dept. of Neurology, Mayo Clinic Rochester, Rochester, MN 55905, USA.Richard J. Caselli - Department of Neurology, Mayo Clinic Scottsdale, Phoenix, AZ 85054, USA.Zbigniew K. Wszolek - Jacksonville CollegeElizabeth Finger - Western UniversityCarol Lippa - Drexel UniversityDavid Lacomis - University of PittsburghHeather Stewart - University of British ColumbiaDennis W. Dickson - Jacksonville CollegeHong Joo Kim - St. Jude Children's Research HospitalEkaterina Rogaeva - University of TorontoEileen Bigio - Northwestern UniversityKevin B. Boylan - Jacksonville CollegeJ. Paul Taylor - Howard Hughes Medical InstituteRosa Rademakers - Mayo Clinic
- Publication Details
- Neuron (Cambridge, Mass.), v 95(4), pp 808-816
- Publisher
- Elsevier
- Resource Type
- Journal article
- Language
- English
- Web of Science ID
- WOS:000407859400012
- Scopus ID
- 2-s2.0-85027355567
- Other Identifier
- 991019312377104721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Neurosciences