期刊
CELL REPORTS
卷 41, 期 3, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.celrep.2022.111508
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资金
- NIH [R35NS097263, R01AG064690, F31NS125681, F32NS116208, 2T32AG047126, S10OD025212]
- Robert Packard Center for ALS Research at Johns Hopkins
- Brain Rejuvenation Project of the Stanford Neurosciences Institute
- Takeda Science Foundation
- NIH/NIDDK [P30DK116074]
A study has found that genes encoding components of the lysosomal vacuolar ATPase (v-ATPase) can modify levels of ataxin-2 protein, and small molecule v-ATPase inhibitors approved by the FDA can lower ataxin-2 protein levels. This discovery suggests v-ATPase as a potential drug target for ALS and SCA2.
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 tar-geting 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 endoge-nous 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-etidro-nate-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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