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

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 (... Full description

Journal Title: Neuron (Cambridge Mass.), 2017-08-16, Vol.95 (4), p.808-816.e9
Main Author: Mackenzie, Ian R
Other Authors: Nicholson, Alexandra M , Sarkar, Mohona , Messing, James , Purice, Maria D , Pottier, Cyril , Annu, Kavya , Baker, Matt , Perkerson, Ralph B , Kurti, Aishe , Matchett, Billie J , Mittag, Tanja , Temirov, Jamshid , Hsiung, Ging-Yuek R , Krieger, Charles , Murray, Melissa E , Kato, Masato , Fryer, John D , Petrucelli, Leonard , Zinman, Lorne , Weintraub, Sandra , Mesulam, Marsel , Keith, Julia , Zivkovic, Sasha A , Hirsch-Reinshagen, Veronica , Roos, Raymond P , Züchner, Stephan , Graff-Radford, Neill R , Petersen, Ronald C , Caselli, Richard J , Wszolek, Zbigniew K , Finger, Elizabeth , Lippa, Carol , Lacomis, David , Stewart, Heather , Dickson, Dennis W , Kim, Hong Joo , Rogaeva, Ekaterina , Bigio, Eileen , Boylan, Kevin B , Taylor, J. Paul , Rademakers, Rosa
Format: Electronic Article Electronic Article
Language: English
Subjects:
Age
RNA
Quelle: Alma/SFX Local Collection
Publisher: United States: Elsevier Inc
ID: ISSN: 0896-6273
Link: https://www.ncbi.nlm.nih.gov/pubmed/28817800
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title: TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics
format: Article
creator:
  • Mackenzie, Ian R
  • Nicholson, Alexandra M
  • Sarkar, Mohona
  • Messing, James
  • Purice, Maria D
  • Pottier, Cyril
  • Annu, Kavya
  • Baker, Matt
  • Perkerson, Ralph B
  • Kurti, Aishe
  • Matchett, Billie J
  • Mittag, Tanja
  • Temirov, Jamshid
  • Hsiung, Ging-Yuek R
  • Krieger, Charles
  • Murray, Melissa E
  • Kato, Masato
  • Fryer, John D
  • Petrucelli, Leonard
  • Zinman, Lorne
  • Weintraub, Sandra
  • Mesulam, Marsel
  • Keith, Julia
  • Zivkovic, Sasha A
  • Hirsch-Reinshagen, Veronica
  • Roos, Raymond P
  • Züchner, Stephan
  • Graff-Radford, Neill R
  • Petersen, Ronald C
  • Caselli, Richard J
  • Wszolek, Zbigniew K
  • Finger, Elizabeth
  • Lippa, Carol
  • Lacomis, David
  • Stewart, Heather
  • Dickson, Dennis W
  • Kim, Hong Joo
  • Rogaeva, Ekaterina
  • Bigio, Eileen
  • Boylan, Kevin B
  • Taylor, J. Paul
  • Rademakers, Rosa
subjects:
  • Adult
  • Age
  • Aged
  • Amyotrophic lateral sclerosis
  • Amyotrophic Lateral Sclerosis - genetics
  • Amyotrophic Lateral Sclerosis - pathology
  • Analysis
  • Article
  • Binding proteins
  • Consortia
  • Dementia
  • Dementia disorders
  • Development and progression
  • Disease
  • Dismantling
  • Disorders
  • DNA-binding protein
  • DNA-Binding Proteins - metabolism
  • Etiology
  • Family Health
  • Female
  • Frontotemporal dementia
  • Frontotemporal Dementia - genetics
  • Frontotemporal Dementia - pathology
  • frontotemporal lobar degeneration
  • Genes
  • Genetic aspects
  • Genetic research
  • Green Fluorescent Proteins - genetics
  • Green Fluorescent Proteins - metabolism
  • HeLa Cells
  • Heterogeneous Nuclear Ribonucleoprotein A1
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B - metabolism
  • Humans
  • liquid-liquid phase separation
  • low-complexity domain
  • Lymphocytes T
  • Male
  • membrane-less organelle
  • mental disorders
  • metabolic diseases
  • Metabolism
  • Microscopy, Confocal
  • Middle Aged
  • Mutation
  • Mutation - genetics
  • Nervous system diseases
  • Neurodegenerative diseases
  • nutritional
  • Pathogenesis
  • Pathology
  • Phase separation
  • Phase transitions
  • Poly(A)-Binding Proteins - genetics
  • Protein binding
  • Proteins
  • Ribonucleic acid
  • RNA
  • RNA-Binding Protein FUS - metabolism
  • stress granules
  • Stress, Physiological - physiology
  • T cell-restricted intracellular antigen-1
  • T cells
  • T-Cell Intracellular Antigen-1
  • TDP-43
  • Time Factors
  • Transfection
ispartof: Neuron (Cambridge, Mass.), 2017-08-16, Vol.95 (4), p.808-816.e9
description: 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.
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 0896-6273
fulltext: fulltext
issn:
  • 0896-6273
  • 1097-4199
url: Link


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titleTIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics
sourceAlma/SFX Local Collection
creatorMackenzie, Ian R ; Nicholson, Alexandra M ; Sarkar, Mohona ; Messing, James ; Purice, Maria D ; Pottier, Cyril ; Annu, Kavya ; Baker, Matt ; Perkerson, Ralph B ; Kurti, Aishe ; Matchett, Billie J ; Mittag, Tanja ; Temirov, Jamshid ; Hsiung, Ging-Yuek R ; Krieger, Charles ; Murray, Melissa E ; Kato, Masato ; Fryer, John D ; Petrucelli, Leonard ; Zinman, Lorne ; Weintraub, Sandra ; Mesulam, Marsel ; Keith, Julia ; Zivkovic, Sasha A ; Hirsch-Reinshagen, Veronica ; Roos, Raymond P ; Züchner, Stephan ; Graff-Radford, Neill R ; Petersen, Ronald C ; Caselli, Richard J ; Wszolek, Zbigniew K ; Finger, Elizabeth ; Lippa, Carol ; Lacomis, David ; Stewart, Heather ; Dickson, Dennis W ; Kim, Hong Joo ; Rogaeva, Ekaterina ; Bigio, Eileen ; Boylan, Kevin B ; Taylor, J. Paul ; Rademakers, Rosa
creatorcontribMackenzie, Ian R ; Nicholson, Alexandra M ; Sarkar, Mohona ; Messing, James ; Purice, Maria D ; Pottier, Cyril ; Annu, Kavya ; Baker, Matt ; Perkerson, Ralph B ; Kurti, Aishe ; Matchett, Billie J ; Mittag, Tanja ; Temirov, Jamshid ; Hsiung, Ging-Yuek R ; Krieger, Charles ; Murray, Melissa E ; Kato, Masato ; Fryer, John D ; Petrucelli, Leonard ; Zinman, Lorne ; Weintraub, Sandra ; Mesulam, Marsel ; Keith, Julia ; Zivkovic, Sasha A ; Hirsch-Reinshagen, Veronica ; Roos, Raymond P ; Züchner, Stephan ; Graff-Radford, Neill R ; Petersen, Ronald C ; Caselli, Richard J ; Wszolek, Zbigniew K ; Finger, Elizabeth ; Lippa, Carol ; Lacomis, David ; Stewart, Heather ; Dickson, Dennis W ; Kim, Hong Joo ; Rogaeva, Ekaterina ; Bigio, Eileen ; Boylan, Kevin B ; Taylor, J. Paul ; Rademakers, Rosa
descriptionAmyotrophic 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.
identifier
0ISSN: 0896-6273
1EISSN: 1097-4199
2DOI: 10.1016/j.neuron.2017.07.025
3PMID: 28817800
languageeng
publisherUnited States: Elsevier Inc
subjectAdult ; Age ; Aged ; Amyotrophic lateral sclerosis ; Amyotrophic Lateral Sclerosis - genetics ; Amyotrophic Lateral Sclerosis - pathology ; Analysis ; Article ; Binding proteins ; Consortia ; Dementia ; Dementia disorders ; Development and progression ; Disease ; Dismantling ; Disorders ; DNA-binding protein ; DNA-Binding Proteins - metabolism ; Etiology ; Family Health ; Female ; Frontotemporal dementia ; Frontotemporal Dementia - genetics ; Frontotemporal Dementia - pathology ; frontotemporal lobar degeneration ; Genes ; Genetic aspects ; Genetic research ; Green Fluorescent Proteins - genetics ; Green Fluorescent Proteins - metabolism ; HeLa Cells ; Heterogeneous Nuclear Ribonucleoprotein A1 ; Heterogeneous-Nuclear Ribonucleoprotein Group A-B - metabolism ; Humans ; liquid-liquid phase separation ; low-complexity domain ; Lymphocytes T ; Male ; membrane-less organelle ; mental disorders ; metabolic diseases ; Metabolism ; Microscopy, Confocal ; Middle Aged ; Mutation ; Mutation - genetics ; Nervous system diseases ; Neurodegenerative diseases ; nutritional ; Pathogenesis ; Pathology ; Phase separation ; Phase transitions ; Poly(A)-Binding Proteins - genetics ; Protein binding ; Proteins ; Ribonucleic acid ; RNA ; RNA-Binding Protein FUS - metabolism ; stress granules ; Stress, Physiological - physiology ; T cell-restricted intracellular antigen-1 ; T cells ; T-Cell Intracellular Antigen-1 ; TDP-43 ; Time Factors ; Transfection
ispartofNeuron (Cambridge, Mass.), 2017-08-16, Vol.95 (4), p.808-816.e9
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02017 Elsevier Inc.
1Copyright © 2017 Elsevier Inc. All rights reserved.
2COPYRIGHT 2017 Elsevier B.V.
3Copyright Elsevier Limited Aug 16, 2017
lds50peer_reviewed
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0Mackenzie, Ian R
1Nicholson, Alexandra M
2Sarkar, Mohona
3Messing, James
4Purice, Maria D
5Pottier, Cyril
6Annu, Kavya
7Baker, Matt
8Perkerson, Ralph B
9Kurti, Aishe
10Matchett, Billie J
11Mittag, Tanja
12Temirov, Jamshid
13Hsiung, Ging-Yuek R
14Krieger, Charles
15Murray, Melissa E
16Kato, Masato
17Fryer, John D
18Petrucelli, Leonard
19Zinman, Lorne
20Weintraub, Sandra
21Mesulam, Marsel
22Keith, Julia
23Zivkovic, Sasha A
24Hirsch-Reinshagen, Veronica
25Roos, Raymond P
26Züchner, Stephan
27Graff-Radford, Neill R
28Petersen, Ronald C
29Caselli, Richard J
30Wszolek, Zbigniew K
31Finger, Elizabeth
32Lippa, Carol
33Lacomis, David
34Stewart, Heather
35Dickson, Dennis W
36Kim, Hong Joo
37Rogaeva, Ekaterina
38Bigio, Eileen
39Boylan, Kevin B
40Taylor, J. Paul
41Rademakers, Rosa
title
0TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics
1Neuron (Cambridge, Mass.)
addtitleNeuron
descriptionAmyotrophic 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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1Age
2Aged
3Amyotrophic lateral sclerosis
4Amyotrophic Lateral Sclerosis - genetics
5Amyotrophic Lateral Sclerosis - pathology
6Analysis
7Article
8Binding proteins
9Consortia
10Dementia
11Dementia disorders
12Development and progression
13Disease
14Dismantling
15Disorders
16DNA-binding protein
17DNA-Binding Proteins - metabolism
18Etiology
19Family Health
20Female
21Frontotemporal dementia
22Frontotemporal Dementia - genetics
23Frontotemporal Dementia - pathology
24frontotemporal lobar degeneration
25Genes
26Genetic aspects
27Genetic research
28Green Fluorescent Proteins - genetics
29Green Fluorescent Proteins - metabolism
30HeLa Cells
31Heterogeneous Nuclear Ribonucleoprotein A1
32Heterogeneous-Nuclear Ribonucleoprotein Group A-B - metabolism
33Humans
34liquid-liquid phase separation
35low-complexity domain
36Lymphocytes T
37Male
38membrane-less organelle
39mental disorders
40metabolic diseases
41Metabolism
42Microscopy, Confocal
43Middle Aged
44Mutation
45Mutation - genetics
46Nervous system diseases
47Neurodegenerative diseases
48nutritional
49Pathogenesis
50Pathology
51Phase separation
52Phase transitions
53Poly(A)-Binding Proteins - genetics
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60Stress, Physiological - physiology
61T cell-restricted intracellular antigen-1
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6Annu, Kavya
7Baker, Matt
8Perkerson, Ralph B
9Kurti, Aishe
10Matchett, Billie J
11Mittag, Tanja
12Temirov, Jamshid
13Hsiung, Ging-Yuek R
14Krieger, Charles
15Murray, Melissa E
16Kato, Masato
17Fryer, John D
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26Züchner, Stephan
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31Finger, Elizabeth
32Lippa, Carol
33Lacomis, David
34Stewart, Heather
35Dickson, Dennis W
36Kim, Hong Joo
37Rogaeva, Ekaterina
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titleTIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics
authorMackenzie, Ian R ; Nicholson, Alexandra M ; Sarkar, Mohona ; Messing, James ; Purice, Maria D ; Pottier, Cyril ; Annu, Kavya ; Baker, Matt ; Perkerson, Ralph B ; Kurti, Aishe ; Matchett, Billie J ; Mittag, Tanja ; Temirov, Jamshid ; Hsiung, Ging-Yuek R ; Krieger, Charles ; Murray, Melissa E ; Kato, Masato ; Fryer, John D ; Petrucelli, Leonard ; Zinman, Lorne ; Weintraub, Sandra ; Mesulam, Marsel ; Keith, Julia ; Zivkovic, Sasha A ; Hirsch-Reinshagen, Veronica ; Roos, Raymond P ; Züchner, Stephan ; Graff-Radford, Neill R ; Petersen, Ronald C ; Caselli, Richard J ; Wszolek, Zbigniew K ; Finger, Elizabeth ; Lippa, Carol ; Lacomis, David ; Stewart, Heather ; Dickson, Dennis W ; Kim, Hong Joo ; Rogaeva, Ekaterina ; Bigio, Eileen ; Boylan, Kevin B ; Taylor, J. Paul ; Rademakers, Rosa
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8Binding proteins
9Consortia
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18Etiology
19Family Health
20Female
21Frontotemporal dementia
22Frontotemporal Dementia - genetics
23Frontotemporal Dementia - pathology
24frontotemporal lobar degeneration
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27Genetic research
28Green Fluorescent Proteins - genetics
29Green Fluorescent Proteins - metabolism
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31Heterogeneous Nuclear Ribonucleoprotein A1
32Heterogeneous-Nuclear Ribonucleoprotein Group A-B - metabolism
33Humans
34liquid-liquid phase separation
35low-complexity domain
36Lymphocytes T
37Male
38membrane-less organelle
39mental disorders
40metabolic diseases
41Metabolism
42Microscopy, Confocal
43Middle Aged
44Mutation
45Mutation - genetics
46Nervous system diseases
47Neurodegenerative diseases
48nutritional
49Pathogenesis
50Pathology
51Phase separation
52Phase transitions
53Poly(A)-Binding Proteins - genetics
54Protein binding
55Proteins
56Ribonucleic acid
57RNA
58RNA-Binding Protein FUS - metabolism
59stress granules
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61T cell-restricted intracellular antigen-1
62T cells
63T-Cell Intracellular Antigen-1
64TDP-43
65Time Factors
66Transfection
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1Nicholson, Alexandra M
2Sarkar, Mohona
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4Purice, Maria D
5Pottier, Cyril
6Annu, Kavya
7Baker, Matt
8Perkerson, Ralph B
9Kurti, Aishe
10Matchett, Billie J
11Mittag, Tanja
12Temirov, Jamshid
13Hsiung, Ging-Yuek R
14Krieger, Charles
15Murray, Melissa E
16Kato, Masato
17Fryer, John D
18Petrucelli, Leonard
19Zinman, Lorne
20Weintraub, Sandra
21Mesulam, Marsel
22Keith, Julia
23Zivkovic, Sasha A
24Hirsch-Reinshagen, Veronica
25Roos, Raymond P
26Züchner, Stephan
27Graff-Radford, Neill R
28Petersen, Ronald C
29Caselli, Richard J
30Wszolek, Zbigniew K
31Finger, Elizabeth
32Lippa, Carol
33Lacomis, David
34Stewart, Heather
35Dickson, Dennis W
36Kim, Hong Joo
37Rogaeva, Ekaterina
38Bigio, Eileen
39Boylan, Kevin B
40Taylor, J. Paul
41Rademakers, Rosa
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10Calcium & Calcified Tissue Abstracts
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jtitleNeuron (Cambridge, Mass.)
delivery
delcategoryRemote Search Resource
fulltextfulltext
addata
au
0Mackenzie, Ian R
1Nicholson, Alexandra M
2Sarkar, Mohona
3Messing, James
4Purice, Maria D
5Pottier, Cyril
6Annu, Kavya
7Baker, Matt
8Perkerson, Ralph B
9Kurti, Aishe
10Matchett, Billie J
11Mittag, Tanja
12Temirov, Jamshid
13Hsiung, Ging-Yuek R
14Krieger, Charles
15Murray, Melissa E
16Kato, Masato
17Fryer, John D
18Petrucelli, Leonard
19Zinman, Lorne
20Weintraub, Sandra
21Mesulam, Marsel
22Keith, Julia
23Zivkovic, Sasha A
24Hirsch-Reinshagen, Veronica
25Roos, Raymond P
26Züchner, Stephan
27Graff-Radford, Neill R
28Petersen, Ronald C
29Caselli, Richard J
30Wszolek, Zbigniew K
31Finger, Elizabeth
32Lippa, Carol
33Lacomis, David
34Stewart, Heather
35Dickson, Dennis W
36Kim, Hong Joo
37Rogaeva, Ekaterina
38Bigio, Eileen
39Boylan, Kevin B
40Taylor, J. Paul
41Rademakers, Rosa
formatjournal
genrearticle
ristypeJOUR
atitleTIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics
jtitleNeuron (Cambridge, Mass.)
addtitleNeuron
date2017-08-16
risdate2017
volume95
issue4
spage808
epage816.e9
pages808-816.e9
issn0896-6273
eissn1097-4199
notes
0These authors contributed equally to this work.
1Lead contact
abstractAmyotrophic 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.
copUnited States
pubElsevier Inc
pmid28817800
doi10.1016/j.neuron.2017.07.025
oafree_for_read