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bioRxiv · 10.1101/2021.12.20.473562

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

Rodriguez, C. M.·Bechek, S. C.·Jones, G. L.·Nakayama, L.·Akiyama, T.·Kim, G.·Solow-Cordero, D. E.·Strittmatter, S. M.·Gitler, A. D.
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Abstract

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.

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Rodriguez, C. M., Bechek, S. C., Jones, G. L., Nakayama, L., Akiyama, T., Kim, G., Solow-Cordero, D. E., Strittmatter, S. M., Gitler, A. D.. 2021-12-21. Targeting RTN4/NoGo-Receptor reduces levels of ALS protein ataxin-2. https://doi.org/10.1101/2021.12.20.473562

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