{"doi":"10.1016/j.celrep.2022.111508","title":"Genome-wide CRISPR screen reveals v-ATPase as a drug target to lower levels of ALS protein ataxin-2","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.","journal":"Cell Reports","year":2022,"id":251456,"datarank":0.8704706945118629,"base_score":3.258096538021482,"endowment":3.258096538021482,"self_citation_contribution":0.4887144807032224,"citation_network_contribution":0.3817562138086405,"self_endowment_contribution":0.4887144807032224,"citer_contribution":0.3817562138086405,"corpus_percentile":null,"corpus_rank":null,"citation_count":25,"citer_count":23,"citers_with_citation_signal":16,"citers_with_endowment":16,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9516,"is_data_producer":true,"deposit_databanks":{"ClinicalTrials.gov":["NCT04494256"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":621945,"name":"Lisa Nakayama","orcid":"0000-0002-3630-3180","position":1,"is_corresponding":false},{"id":621943,"name":"Jacob A. Blum","orcid":"0000-0002-7015-6815","position":2,"is_corresponding":false},{"id":822849,"name":"Tetsuya Akiyama","orcid":"0000-0002-8076-1242","position":3,"is_corresponding":false},{"id":347568,"name":"Steven Boeynaems","orcid":"0000-0002-9705-9871","position":4,"is_corresponding":false},{"id":473283,"name":"Meenakshi Chakraborty","orcid":"0000-0001-8985-7219","position":5,"is_corresponding":false},{"id":236132,"name":"Julien Couthouis","orcid":"0000-0002-2378-4595","position":6,"is_corresponding":false},{"id":230689,"name":"Eduardo Tassoni-Tsuchida","orcid":"0000-0001-8062-6027","position":7,"is_corresponding":false},{"id":805536,"name":"Caitlin M. Rodriguez","orcid":"0000-0002-3827-6753","position":8,"is_corresponding":false},{"id":62612,"name":"Michael C. Bassik","orcid":"0000-0001-5185-8427","position":9,"is_corresponding":false},{"id":230690,"name":"Aaron D. Gitler","orcid":"0000-0001-8603-1526","position":10,"is_corresponding":false},{"id":230688,"name":"Garam Kım","orcid":"0000-0001-5907-1127","position":0,"is_corresponding":true}],"reference_count":40,"raw_metadata":null,"created_at":"2026-07-19T00:24:41.993282Z","pmid":"36288714","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}