@article{556642038c484765b79d928af6e34f46,
title = "TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics",
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",
author = "Mackenzie, {Ian R.} and Nicholson, {Alexandra M.} and Mohona Sarkar and James Messing and Purice, {Maria D.} and Cyril Pottier and Kavya Annu and Matt Baker and Perkerson, {Ralph B.} and Aishe Kurti and Matchett, {Billie J.} and Tanja Mittag and Jamshid Temirov and Hsiung, {Ging Yuek R.} and Charles Krieger and Murray, {Melissa E.} and Masato Kato and Fryer, {John D.} and Leonard Petrucelli and Lorne Zinman and Sandra Weintraub and Marsel Mesulam and Julia Keith and Zivkovic, {Sasha A.} and Veronica Hirsch-Reinshagen and Roos, {Raymond P.} and Stephan Z{\"u}chner and Graff-Radford, {Neill R.} and Petersen, {Ronald C.} and Caselli, {Richard J.} and Wszolek, {Zbigniew K.} and Elizabeth Finger and Carol Lippa and David Lacomis and Heather Stewart and Dickson, {Dennis W.} and Kim, {Hong Joo} and Ekaterina Rogaeva and Eileen Bigio and Boylan, {Kevin B.} and Taylor, {J. Paul} and Rosa Rademakers",
note = "Funding Information: This study used ALS samples from the NINDS Human Genetics Resource Center DNA and Cell Line Repository (https://ccr.coriell.org/ninds). This work was supported by the Mayo Clinic for Individualized Medicine, the Arizona Alzheimer's Consortium, the Howard Hughes Medical Institute (045104-Taylor), the Clinical Research in ALS and related disorders for Therapeutic Development (CReATe) Consortium (1U54NS092091), the Canadian Institutes for Health Research (74580), and NIH grants R35NS097974, R35NS097261, R35NS097273, P50AG016574, P50NS072187, P01NS084974, U01AG006576, U54NS092091, P30AG019610, R01AG031581, R01NS072248, and R01NS075764. This work was supported in part by the Canadian Consortium on Neurodegeneration in Aging (137794) and the ALS Canada-Brain Canada Hudson Grant. A.M.N. was supported by the Richard C. Kendall Fellowship and C.P. is supported by the Younkin Fellowship. The authors also thank Anderson Kanagaraj, Tammee M. Parsons, NiCole A. Finch, Nicole Milkovic, Mieu Brooks, Thomas Ravenscroft, Bruce Eckloff, Monica Castanedes-Casey, Virginia Phillips, Linda Rousseau, and Yingxue Ren for technical and bioinformatic assistance; Steve McKnight for access to transmission electron microscopy; and Regina-Maria Kolaitis for assistance with live-cell imaging. The authors also thank Natalia Nedelsky for manuscript editing and Ana M. Caputo, Pamela Desaro, Carla Palmucci, Amelia Robertson, Audrey Strongosky, Marife Fabros, and Pheth Sengdy for assistance with patient ascertainment. Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",
year = "2017",
month = aug,
day = "16",
doi = "10.1016/j.neuron.2017.07.025",
language = "English (US)",
volume = "95",
pages = "808--816.e9",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "4",
}