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Neuron. 2017 Aug 16;95(4):808-816.e9. doi: 10.1016/j.neuron.2017.07.025.

TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics.

Author information

1
Department of Pathology and Laboratory Medicine, Vancouver Coastal Health and the University of British Colombia, Vancouver, BC V6T 2B5, Canada.
2
Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL 32224, USA.
3
Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
4
Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
5
Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
6
Division of Neurology, Vancouver Coastal Health and the University of British Columbia, Vancouver, BC V6T 2B5, Canada.
7
Division of Neurology, Vancouver Coastal Health and the University of British Columbia, Vancouver, BC V6T 2B5, Canada; Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC V5A 1S6, Canada.
8
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
9
Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada.
10
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
11
Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A1, Canada.
12
Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
13
Department of Neurology, University of Chicago Medicine, Chicago, IL 60637, USA.
14
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.
15
Department of Neurology, Mayo Clinic Jacksonville, Jacksonville, FL 32224, USA.
16
Department of Neurology, Mayo Clinic Rochester, Rochester, MN 55905, USA.
17
Department of Neurology, Mayo Clinic Scottsdale, Phoenix, AZ 85054, USA.
18
Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON N6A 5C1, Canada.
19
Department of Neurology, Drexel University College of Medicine, Philadelphia, PA 19107, USA; Department of Neurology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
20
Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
21
Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON M5T 2S8, Canada.
22
Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
23
Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: jpaul.taylor@stjude.org.
24
Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL 32224, USA. Electronic address: rademakers.rosa@mayo.edu.

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.

KEYWORDS:

T cell-restricted intracellular antigen-1; TDP-43; amyotrophic lateral sclerosis; frontotemporal dementia; frontotemporal lobar degeneration; liquid-liquid phase separation; low-complexity domain; membrane-less organelle; stress granules

PMID:
28817800
PMCID:
PMC5576574
DOI:
10.1016/j.neuron.2017.07.025
[Indexed for MEDLINE]
Free PMC Article

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