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

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 ZinmanSandra 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

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English (US)
Pages (from-to)	808-816.e9
Journal	Neuron
Volume	95
Issue number	4
DOIs	https://doi.org/10.1016/j.neuron.2017.07.025
State	Published - Aug 16 2017

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

ASJC Scopus subject areas

General Neuroscience

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10.1016/j.neuron.2017.07.025

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Mackenzie, I. R., Nicholson, A. M., Sarkar, M., Messing, J., Purice, M. D., Pottier, C., Annu, K., Baker, M., Perkerson, R. B., Kurti, A., Matchett, B. J., Mittag, T., Temirov, J., Hsiung, G. Y. R., Krieger, C., Murray, M. E., Kato, M., Fryer, J. D., Petrucelli, L., ... Rademakers, R. (2017). TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics. Neuron, 95(4), 808-816.e9. https://doi.org/10.1016/j.neuron.2017.07.025

Mackenzie, IR, Nicholson, AM, Sarkar, M, Messing, J, Purice, MD, Pottier, C, Annu, K, Baker, M, Perkerson, RB, Kurti, A, Matchett, BJ, Mittag, T, Temirov, J, Hsiung, GYR, Krieger, C, Murray, ME, Kato, M, Fryer, JD, Petrucelli, L, Zinman, L, Weintraub, S, Mesulam, M, Keith, J, Zivkovic, SA, Hirsch-Reinshagen, V, Roos, RP, Züchner, S, Graff-Radford, NR, Petersen, RC, Caselli, RJ, Wszolek, ZK, Finger, E, Lippa, C, Lacomis, D, Stewart, H, Dickson, DW, Kim, HJ, Rogaeva, E, Bigio, E, Boylan, KB, Taylor, JP & Rademakers, R 2017, 'TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics', Neuron, vol. 95, no. 4, pp. 808-816.e9. https://doi.org/10.1016/j.neuron.2017.07.025

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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",

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doi = "10.1016/j.neuron.2017.07.025",

language = "English (US)",

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AU - Mackenzie, Ian R.

AU - Nicholson, Alexandra M.

AU - Sarkar, Mohona

AU - Messing, James

AU - Purice, Maria D.

AU - Pottier, Cyril

AU - Annu, Kavya

AU - Baker, Matt

AU - Perkerson, Ralph B.

AU - Kurti, Aishe

AU - Matchett, Billie J.

AU - Mittag, Tanja

AU - Temirov, Jamshid

AU - Hsiung, Ging Yuek R.

AU - Krieger, Charles

AU - Murray, Melissa E.

AU - Kato, Masato

AU - Fryer, John D.

AU - Petrucelli, Leonard

AU - Zinman, Lorne

AU - Weintraub, Sandra

AU - Mesulam, Marsel

AU - Keith, Julia

AU - Zivkovic, Sasha A.

AU - Hirsch-Reinshagen, Veronica

AU - Roos, Raymond P.

AU - Züchner, Stephan

AU - Graff-Radford, Neill R.

AU - Petersen, Ronald C.

AU - Caselli, Richard J.

AU - Wszolek, Zbigniew K.

AU - Finger, Elizabeth

AU - Lippa, Carol

AU - Lacomis, David

AU - Stewart, Heather

AU - Dickson, Dennis W.

AU - Kim, Hong Joo

AU - Rogaeva, Ekaterina

AU - Bigio, Eileen

AU - Boylan, Kevin B.

AU - Taylor, J. Paul

AU - Rademakers, Rosa

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N2 - 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.

AB - 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.

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KW - frontotemporal dementia

KW - frontotemporal lobar degeneration

KW - liquid-liquid phase separation

KW - low-complexity domain

KW - membrane-less organelle

KW - stress granules

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ER -

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

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