Genome-wide CRISPR screen reveals v-ATPase as a drug target to lower levels of ALS protein ataxin-2

ATXN2 has emerged as an exciting therapeutic target for neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxia type 2 (SCA2), as lowering its levels via genomic knockout or anti-sense oligonucleotide (ASO) treatment has been shown to mitigate disease phenotypes and led to a current clinical trial of ATXN2 ASOs for treatment of ALS in humans. To identify additional ways to lower ataxin-2 protein levels, we performed a genome-wide fluorescence activated cell sorting (FACS)-based CRISPR screen in human cells and identified multiple components of the lysosomal vacuolar ATPase (v-ATPase) as modifiers of ataxin-2 levels. This dataset contains the RNA-sequencing data and CRISPR screen data used to support the conclusions from this study. Overall design: Transcriptional changes in ATP6V1A siRNA knockdown compared to non-targeting siRNA condition in HeLa cells. Differential gene expressoin derived from RNA-sequencing data, analyzed using DESeq2. Additionally, results of FACS-based CRISPR genome-wide knockout screen data (gene knockouts that increase or decrease ataxin-2 protein levels).