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

Autor:	Lorne Zinman, Carol F. Lippa, Ralph B. Perkerson, David Lacomis, Aishe Kurti, Billie J. Matchett, Cyril Pottier, J. Paul Taylor, Hong Joo Kim, Eileen H. Bigio, Heather Stewart, Zbigniew K. Wszolek, Leonard Petrucelli, M.-Marsel Mesulam, Elizabeth Finger, Kavya Annu, Ronald C. Petersen, Jamshid Temirov, Tanja Mittag, Charles Krieger, Rosa Rademakers, James Messing, Veronica Hirsch-Reinshagen, Ian R. A. Mackenzie, Sasha Zivkovic, Stephan Züchner, Alexandra M. Nicholson, Julia Keith, Ekaterina Rogaeva, Dennis W. Dickson, Neill R. Graff-Radford, Richard J. Caselli, Matt Baker, Melissa E. Murray, Kevin B. Boylan, Sandra Weintraub, Ging-Yuek Robin Hsiung, Masato Kato, Raymond P. Roos, John D. Fryer, Maria D. Purice, Mohona Sarkar
Rok vydání:	2017
Předmět:	Adult Male 0301 basic medicine Pathology medicine.medical_specialty Time Factors TIA1 Heterogeneous Nuclear Ribonucleoprotein A1 Green Fluorescent Proteins Neuropathology Biology Transfection medicine.disease_cause Poly(A)-Binding Proteins Article Pathogenesis 03 medical and health sciences Stress granule Stress Physiological Heterogeneous-Nuclear Ribonucleoprotein Group A-B mental disorders medicine Humans Amyotrophic lateral sclerosis Aged Family Health Genetics Mutation Microscopy Confocal General Neuroscience Amyotrophic Lateral Sclerosis nutritional and metabolic diseases Frontotemporal lobar degeneration Middle Aged medicine.disease T-Cell Intracellular Antigen-1 nervous system diseases 3. Good health DNA-Binding Proteins 030104 developmental biology Frontotemporal Dementia RNA-Binding Protein FUS Female Human medicine HeLa Cells Frontotemporal dementia
Zdroj:	Neuron
ISSN:	0896-6273
DOI:	10.1016/j.neuron.2017.07.025
Popis:	Summary 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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b24545e056391b536f1d854718beeba0 https://doi.org/10.1016/j.neuron.2017.07.025 Zobrazit plný text záznamu