Genome-wide CRISPR screen reveals v-ATPase as a drug target to lower levels of ALS protein ataxin-2.
ALS
CP: Neuroscience
FACS
SCA2
TDP-43
ataxin-2
bisphosphonate
etidronate
genetic screens
small-molecule therapy
v-ATPase
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
25 10 2022
25 10 2022
Historique:
received:
15
12
2021
revised:
20
05
2022
accepted:
22
09
2022
entrez:
26
10
2022
pubmed:
27
10
2022
medline:
29
10
2022
Statut:
ppublish
Résumé
Mutations in the ataxin-2 gene (ATXN2) cause the neurodegenerative disorders amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxia type 2 (SCA2). A therapeutic strategy using antisense oligonucleotides targeting ATXN2 has entered clinical trial in humans. Additional ways to decrease ataxin-2 levels could lead to cheaper or less invasive therapies and elucidate how ataxin-2 is normally regulated. Here, we perform a genome-wide fluorescence-activated cell sorting (FACS)-based CRISPR-Cas9 screen in human cells and identify genes encoding components of the lysosomal vacuolar ATPase (v-ATPase) as modifiers of endogenous ataxin-2 protein levels. Multiple FDA-approved small molecule v-ATPase inhibitors lower ataxin-2 protein levels in mouse and human neurons, and oral administration of at least one of these drugs-etidronate-is sufficient to decrease ataxin-2 in the brains of mice. Together, we propose v-ATPase as a drug target for ALS and SCA2 and demonstrate the value of FACS-based screens in identifying genetic-and potentially druggable-modifiers of human disease proteins.
Identifiants
pubmed: 36288714
pii: S2211-1247(22)01358-4
doi: 10.1016/j.celrep.2022.111508
pmc: PMC9664452
mid: NIHMS1845179
pii:
doi:
Substances chimiques
Ataxin-2
0
Vacuolar Proton-Translocating ATPases
EC 3.6.1.-
Pharmaceutical Preparations
0
Etidronic Acid
M2F465ROXU
Oligonucleotides, Antisense
0
Banques de données
ClinicalTrials.gov
['NCT04494256']
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
111508Subventions
Organisme : NINDS NIH HHS
ID : F32 NS116208
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK116074
Pays : United States
Organisme : NIH HHS
ID : S10 OD025212
Pays : United States
Organisme : NINDS NIH HHS
ID : F31 NS125681
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG064690
Pays : United States
Organisme : NIA NIH HHS
ID : T32 AG047126
Pays : United States
Organisme : NINDS NIH HHS
ID : R35 NS097263
Pays : United States
Informations de copyright
Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests A.D.G. is a scientific founder of Maze Therapeutics. Stanford University has filed a provisional patent (63/286,436) on methods described in this manuscript for treatment of neurodegenerative diseases through the inhibition of ataxin-2.
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