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

• Published in: Cell reports (Cambridge) Vol. 41; no. 4; p. 111505
• Main Authors: Rodriguez, Caitlin M., Bechek, Sophia C., Jones, Graham L., Nakayama, Lisa, Akiyama, Tetsuya, Kim, Garam, Solow-Cordero, David E., Strittmatter, Stephen M., Gitler, Aaron D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.10.2022
• Subjects: ALS; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Animals; ataxin-2; Ataxin-2 - genetics; genetic screens; Humans; Mice; Mice, Knockout; Nogo Proteins - genetics; Nogo Proteins - metabolism; Nogo Receptors - metabolism; NoGo-receptor; Peptides - metabolism; RNA, Small Interfering; RTN4R; SCA2; Spinocerebellar Ataxias - genetics; TDP-43; RTN4R; ataxin-2; CP: Neuroscience; TDP-43; SCA2; ALS; genetic screens; NoGo-receptor
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.111505

Gene-based therapeutic strategies to lower ataxin-2 levels are emerging for the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxia type 2 (SCA2). Additional strategies to lower levels of ataxin-2 could be beneficial. Here, we perform a genome-wide arrayed small interfering RNA (siRNA) screen in human cells and identify RTN4R, the gene encoding the RTN4/NoGo-Receptor, as a potent modifier of ataxin-2 levels. RTN4R knockdown, or treatment with a peptide inhibitor, is 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. We provide evidence 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. [Display omitted] •Whole-genome siRNA screen in human cells identifies regulators of ataxin-2 levels•siRNA targets that decrease ataxin-2 are enriched for proteins with an LSm domain•RTN4/NoGo-Receptor knockdown or peptide inhibition in neurons reduces ataxin-2•Knockdown of ataxin-2 in primary neurons increases regeneration after axotomy Rodriguez et al. perform a screen for regulators of the ALS protein ataxin-2. Knockdown or peptide inhibition of RTN4/NoGo-receptor decreases levels of ataxin-2. Further study shows that ataxin-2 shares a role with RTN4/NoGo-Receptor in limiting axonal regeneration.