RT Journal Article
SR Electronic
T1 Small molecule v-ATPase inhibitor Etidronate lowers levels of ALS protein ataxin-2
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.12.20.473567
DO 10.1101/2021.12.20.473567
A1 Garam Kim
A1 Lisa Nakayama
A1 Jacob A. Blum
A1 Tetsuya Akiyama
A1 Steven Boeynaems
A1 Meena Chakraborty
A1 Julien Couthouis
A1 Eduardo Tassoni-Tsuchida
A1 Caitlin M. Rodriguez
A1 Michael C. Bassik
A1 Aaron D. Gitler
YR 2021
UL http://biorxiv.org/content/early/2021/12/21/2021.12.20.473567.abstract
AB Antisense oligonucleotide therapy targeting ATXN2—a gene in which mutations cause neurodegenerative diseases spinocerebellar ataxia type 2 and amyotrophic lateral sclerosis—has entered clinical trials in humans. Additional methods to lower ataxin-2 levels would be beneficial not only in uncovering potentially cheaper or less invasive therapies, but also in gaining greater mechanistic insight into how ataxin-2 is normally regulated. We performed a genome-wide fluorescence activated cell sorting (FACS)-based CRISPR screen in human cells and identified multiple subunits of the lysosomal vacuolar ATPase (v-ATPase) as regulators of ataxin-2 levels. We demonstrate that Etidronate—a U.S. Food and Drug Administration (FDA)-approved drug that inhibits the v-ATPase—lowers ataxin-2 protein levels in mouse and human neurons. Moreover, oral administration of the drug to mice in their water supply and food is sufficient to lower ataxin-2 levels in the brain. Thus, we uncover Etidronate as a safe and inexpensive compound for lowering ataxin-2 levels and demonstrate the utility of FACS-based screens for identifying targets to modulate levels of human disease proteins.Competing Interest StatementA.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.