Disruption of ER-mitochondria tethering and signalling in C9orf72-associated amyotrophic lateral sclerosis and frontotemporal dementia.
C9orf72
GSK3β
PTPIP51
VAPB
amyotrophic lateral sclerosis
endoplasmic reticulum
frontotemporal dementia
mitochondria
Journal
Aging cell
ISSN: 1474-9726
Titre abrégé: Aging Cell
Pays: England
ID NLM: 101130839
Informations de publication
Date de publication:
02 2022
02 2022
Historique:
revised:
21
12
2021
received:
12
07
2021
accepted:
24
12
2021
pubmed:
14
1
2022
medline:
5
4
2022
entrez:
13
1
2022
Statut:
ppublish
Résumé
Hexanucleotide repeat expansions in C9orf72 are the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The mechanisms by which the expansions cause disease are not properly understood but a favoured route involves its translation into dipeptide repeat (DPR) polypeptides, some of which are neurotoxic. However, the precise targets for mutant C9orf72 and DPR toxicity are not fully clear, and damage to several neuronal functions has been described. Many of these functions are regulated by signalling between the endoplasmic reticulum (ER) and mitochondria. ER-mitochondria signalling requires close physical contacts between the two organelles that are mediated by the VAPB-PTPIP51 'tethering' proteins. Here, we show that ER-mitochondria signalling and the VAPB-PTPIP51 tethers are disrupted in neurons derived from induced pluripotent stem (iPS) cells from patients carrying ALS/FTD pathogenic C9orf72 expansions and in affected neurons in mutant C9orf72 transgenic mice. In these mice, disruption of the VAPB-PTPIP51 tethers occurs prior to disease onset suggesting that it contributes to the pathogenic process. We also show that neurotoxic DPRs disrupt the VAPB-PTPIP51 interaction and ER-mitochondria contacts and that this may involve activation of glycogen synthase kinases-3β (GSK3β), a known negative regulator of VAPB-PTPIP51 binding. Finally, we show that these DPRs disrupt delivery of Ca
Identifiants
pubmed: 35026048
doi: 10.1111/acel.13549
pmc: PMC8844122
doi:
Substances chimiques
C9orf72 Protein
0
C9orf72 protein, human
0
Mitochondrial Proteins
0
PTPIP51 protein, mouse
EC 3.1.3.48
Protein Tyrosine Phosphatases
EC 3.1.3.48
Calcium
SY7Q814VUP
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e13549Subventions
Organisme : Motor Neurone Disease Association
ID : MILLER/OCT12/863-792
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/R022666/1
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
Informations de copyright
© 2022 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
Références
Neuron. 2019 Mar 20;101(6):1057-1069
pubmed: 30897357
Neuron. 2011 Oct 20;72(2):245-56
pubmed: 21944778
EMBO Mol Med. 2016 Dec 1;8(12):1421-1437
pubmed: 27821430
Hum Mol Genet. 2013 Nov 15;22(22):4646-52
pubmed: 23825109
Neurobiol Dis. 2020 Sep;143:105020
pubmed: 32682953
Nat Rev Neurol. 2018 Sep;14(9):544-558
pubmed: 30120348
Acta Neuropathol Commun. 2019 Mar 6;7(1):35
pubmed: 30841933
Nat Commun. 2014 Jun 03;5:3996
pubmed: 24893131
Brain. 2015 Apr;138(Pt 4):875-90
pubmed: 25678561
Neuron. 2011 Oct 20;72(2):257-68
pubmed: 21944779
Curr Biol. 2017 Feb 6;27(3):371-385
pubmed: 28132811
Aging Cell. 2022 Feb;21(2):e13549
pubmed: 35026048
Nat Commun. 2019 Aug 19;10(1):3726
pubmed: 31427578
Neuron. 2014 Dec 17;84(6):1213-25
pubmed: 25521377
Nat Rev Mol Cell Biol. 2012 Oct;13(10):607-25
pubmed: 22992592
Cell Calcium. 2021 Sep;98:102453
pubmed: 34399235
Cell Calcium. 2012 Jul;52(1):44-51
pubmed: 22459281
Nat Methods. 2006 Dec;3(12):995-1000
pubmed: 17072308
Acta Neuropathol. 2017 Aug;134(2):187-205
pubmed: 28401333
Trends Neurosci. 2016 Mar;39(3):146-157
pubmed: 26899735
Acta Neuropathol. 2020 Nov;140(5):625-643
pubmed: 32876811
Neuron. 2013 Aug 7;79(3):416-38
pubmed: 23931993
Acta Neuropathol Commun. 2019 May 8;7(1):73
pubmed: 31068217
Hum Mol Genet. 2012 Mar 15;21(6):1299-311
pubmed: 22131369
EMBO Mol Med. 2018 Jan;10(1):22-31
pubmed: 29113975
Neuron. 2016 May 4;90(3):535-50
pubmed: 27112497
Science. 2014 Sep 5;345(6201):1139-45
pubmed: 25081482
Proc Natl Acad Sci U S A. 2013 May 7;110(19):7916-21
pubmed: 23620518
Trends Cell Biol. 2018 Jul;28(7):523-540
pubmed: 29588129
J Comp Neurol. 1999 Apr 5;406(2):207-20
pubmed: 10096607
Brain. 2021 Sep 17;:
pubmed: 34534264
Science. 2017 Nov 3;358(6363):623-630
pubmed: 29097544
Hum Mol Genet. 2016 Sep 1;25(17):3741-3753
pubmed: 27402882
Stem Cells. 2016 Aug;34(8):2063-78
pubmed: 27097283
Science. 2014 Sep 5;345(6201):1192-1194
pubmed: 25103406
Cell. 2016 Oct 20;167(3):774-788.e17
pubmed: 27768896
Stem Cell Reports. 2020 May 12;14(5):892-908
pubmed: 32330447
Cell Death Dis. 2018 Feb 28;9(3):327
pubmed: 29491392
EMBO J. 2020 Oct 1;39(19):e103530
pubmed: 33001475
Hum Mol Genet. 2017 Dec 15;26(24):4765-4777
pubmed: 28973350
Front Mol Neurosci. 2011 Nov 16;4:40
pubmed: 22110425
J Cell Biol. 2006 Sep 25;174(7):915-21
pubmed: 16982799
EMBO Rep. 2016 Sep;17(9):1326-42
pubmed: 27418313
Sci Adv. 2021 Apr 9;7(15):
pubmed: 33837088
Science. 2006 Oct 6;314(5796):130-3
pubmed: 17023659
Acta Neuropathol. 2017 Jul;134(1):129-149
pubmed: 28337542