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

Ian R Mackenzie; Alexandra M Nicholson; Mohona Sarkar; James Messing; Maria D Purice; Cyril Pottier; Kavya Annu; Matt Baker; Ralph B Perkerson; Aishe Kurti; Billie J Matchett; Tanja Mittag; Jamshid Temirov; Ging-Yuek R Hsiung; Charles Krieger; Melissa E Murray; Masato Kato; John D Fryer; Leonard Petrucelli; Lorne Zinman; Sandra Weintraub; Marsel Mesulam; Julia Keith; Sasha A Zivkovic; Veronica Hirsch-Reinshagen; Raymond P Roos; Stephan Züchner; Neill R Graff-Radford; Ronald C Petersen; Richard J Caselli; Zbigniew K Wszolek; Elizabeth Finger; Carol Lippa; David Lacomis; Heather Stewart; Dennis W Dickson; Hong Joo Kim; Ekaterina Rogaeva; Eileen Bigio; Kevin B Boylan; J. Paul Taylor; Rosa Rademakers

doi:10.1016/j.neuron.2017.07.025

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

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

Ian R Mackenzie, Alexandra M Nicholson, Mohona Sarkar, James Messing, Maria D Purice, Cyril Pottier, Kavya Annu, Matt Baker, Ralph B Perkerson, Aishe Kurti, …

Neuron (Cambridge, Mass.), Vol.95(4), pp.808-816.e9

2017-08-16

DOI: https://doi.org/10.1016/j.neuron.2017.07.025

PMCID: PMC5576574

PMID: 28817800

Abstract

low-complexity domain

liquid-liquid phase separation

TDP-43

T cell-restricted intracellular antigen-1

stress granules

frontotemporal dementia

amyotrophic lateral sclerosis

membrane-less organelle

frontotemporal lobar degeneration

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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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.52 Neurodegenerative Diseases; 1.52.765 Amyotrophic Lateral Sclerosis
Web Of Science research areas: Neurosciences
ESI research areas: Neuroscience & Behavior

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Title: TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics
Creators: Ian R Mackenzie - Department of Pathology and Laboratory Medicine, Vancouver Coastal Health and the University of British Colombia, Vancouver, BC V6T 2B5, Canada
Alexandra M Nicholson - Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL 32224, USA
Mohona Sarkar - Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
James Messing - Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Maria D Purice - Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Cyril Pottier - Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL 32224, USA
Kavya Annu - Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Matt Baker - Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL 32224, USA
Ralph B Perkerson - Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL 32224, USA
Aishe Kurti - Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL 32224, USA
Billie J Matchett - Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL 32224, USA
Tanja Mittag - Department of Structural Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Jamshid Temirov - Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Ging-Yuek R Hsiung - Division of Neurology, Vancouver Coastal Health and the University of British Columbia, Vancouver, BC V6T 2B5, Canada
Charles Krieger - Division of Neurology, Vancouver Coastal Health and the University of British Columbia, Vancouver, BC V6T 2B5, Canada
Melissa E Murray - Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL 32224, USA
Masato Kato - Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
John D Fryer - Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL 32224, USA
Leonard Petrucelli - Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL 32224, USA
Lorne Zinman - Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada
Sandra Weintraub - Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Marsel Mesulam - Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Julia Keith - Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada
Sasha A Zivkovic - Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
Veronica Hirsch-Reinshagen - Department of Pathology and Laboratory Medicine, Vancouver Coastal Health and the University of British Colombia, Vancouver, BC V6T 2B5, Canada
Raymond P Roos - Department of Neurology, University of Chicago Medicine, Chicago, IL 60637, USA
Stephan 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 - Department of Neurology, Mayo Clinic Jacksonville, Jacksonville, FL 32224, USA
Ronald C Petersen - Department 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 - Department of Neurology, Mayo Clinic Jacksonville, Jacksonville, FL 32224, USA
Elizabeth Finger - Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON N6A 5C1, Canada
Carol Lippa - Department of Neurology, Drexel University College of Medicine, Philadelphia, PA 19107, USA
David Lacomis - Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
Heather Stewart - Division of Neurology, Vancouver Coastal Health and the University of British Columbia, Vancouver, BC V6T 2B5, Canada
Dennis W Dickson - Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL 32224, USA
Hong Joo Kim - Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Ekaterina Rogaeva - Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON M5T 2S8, Canada
Eileen Bigio - Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Kevin B Boylan - Department of Neurology, Mayo Clinic Jacksonville, Jacksonville, FL 32224, USA
J. Paul Taylor - Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Rosa Rademakers - Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL 32224, USA
Publication Details: Neuron (Cambridge, Mass.), Vol.95(4), pp.808-816.e9
Publisher: Elsevier Inc
Academic Unit: Leadership Department; Miller School of Medicine; John P. Hussman Institute for Human Genomics
Language: English
Resource Type: Journal article
PMID: 28817800
PMCID: PMC5576574
Record Identifier: 991031575964602976