ArticleCell reports2022
Genome-wide CRISPR screen reveals v-ATPase as a drug target to lower levels of ALS protein ataxin-2.
Article in Cell reports, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 24 citations in OpenAlex.
- PAICS mediates DNA damage and cerebellar neuronal loss in C9orf72 amyotrophic lateral sclerosis.Brain : a journal of neurology · 2026Article
- Dissecting the relationship between haplotypes around ATXN2 CAG repeats and the number of CAA interruptions by long-read sequencing.medRxiv : the preprint server for health sciences · 2026Article
- CRISPR-based functional genomic screening in neurodegeneration: mechanistic insights into AD, PD, and ALS.Frontiers in aging neuroscience · 2026Review
- Multiomics approach identifies SERPINB1 as candidate biomarker for spinocerebellar ataxia type 2.Scientific reports · 2025Article
- Protein kinases in neurodegenerative diseases: current understandings and implications for drug discovery.Signal transduction and targeted therapy · 2025Review
- Ataxin-2 polyglutamine expansions aberrantly sequester TDP-43 ribonucleoprotein condensates disrupting mRNA transport and local translation in neurons.Developmental cell · 2025Article
- CRISPR-Cas technologies in neurodegenerative disorders: mechanistic insights, therapeutic potential, and translational challenges.Frontiers in neurology · 2025Review
- Rare association between spinocerebellar ataxia and amyotrophic lateral sclerosis: a case series.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2024Article
- Review
- Structured and disordered regions of Ataxin-2 contribute differently to the specificity and efficiency of mRNP granule formation.PLoS genetics · 2024Article
- Small-molecule correctors divert CFTR-F508del from ERAD by stabilizing sequential folding states.Molecular biology of the cell · 2024Article
- Modeling sporadic juvenile ALS in iPSC-derived motor neurons explores the pathogenesis of FUSFrontiers in cellular neuroscience · 2024Article
- Deciphering the interactome of Ataxin-2 and TDP-43 in iPSC-derived neurons for potential ALS targets.PloS one · 2024Article
- Regulators of mitonuclear balance link mitochondrial metabolism to mtDNA expression.Nature cell biology · 2023Article
- Targeting RTN4/NoGo-Receptor reduces levels of ALS protein ataxin-2.Cell reports · 2022Article
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.