Targeting RTN4/NoGo-Receptor reduces levels of ALS protein ataxin-2

Gene-based therapeutic strategies to lower ataxin-2 levels are emerging for neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxia type 2 (SCA2). To identify additional ways of reducing ataxin-2 levels, we performed a genome-wide screen in human cells for regulators of ataxin-2 and identified RTN4R , the gene encoding the RTN4/NoGo-Receptor, as a top hit. RTN4R knockdown, or treatment with a peptide inhibitor, was sufficient to lower ataxin-2 protein levels in mouse and human neurons in vitro and Rtn4r knockout mice have reduced ataxin-2 levels in vivo . Remarkably, we observed that ataxin-2 shares a role with the RTN4/NoGo-Receptor in limiting axonal regeneration. Reduction of either protein increases axonal regrowth following axotomy. These data define the RTN4/NoGo-Receptor as a novel therapeutic target for ALS and SCA2 and implicate the targeting of ataxin-2 as a potential treatment following nerve injury. ### Competing Interest Statement A.D.G. is a scientific founder of Maze Therapeutics. S.M.S. is a founder and equity holder in ReNetX Bio, Inc. which seeks clinical development of the decoy receptor, NgR1-Fc (AXER-204), for chronic spinal cord injury treatment. 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.