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

Cell Rep. 2022 Oct 25;41(4):111505. 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.

Keywords: ALS; CP: Neuroscience; NoGo-receptor; RTN4R; SCA2; TDP-43; ataxin-2; genetic screens.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Amyotrophic Lateral Sclerosis* / genetics
  • Amyotrophic Lateral Sclerosis* / metabolism
  • Animals
  • Ataxin-2 / genetics
  • Humans
  • Mice
  • Mice, Knockout
  • Nogo Proteins / genetics
  • Nogo Proteins / metabolism
  • Nogo Receptors / metabolism
  • Peptides / metabolism
  • RNA, Small Interfering
  • Spinocerebellar Ataxias* / genetics


  • Ataxin-2
  • RNA, Small Interfering
  • Nogo Receptors
  • Peptides
  • RTN4 protein, human
  • Nogo Proteins