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

Cell Reports, 2022 · DOI: 10.1016/j.celrep.2022.111505 · Published: October 25, 2022

Simple Explanation

This study identifies a new way to lower levels of ataxin-2, a protein linked to ALS and SCA2. The researchers found that targeting the RTN4/NoGo-Receptor can reduce ataxin-2 levels. The RTN4/NoGo-Receptor is involved in nerve regeneration. The research showed that reducing either RTN4/NoGo-Receptor or ataxin-2 promotes nerve regrowth after injury. These findings suggest that targeting ataxin-2 could be a new therapeutic approach for ALS, SCA2, and potentially nerve injuries.

Study Duration

Not specified

Participants

Mouse and human neurons in vitro, Rtn4r knockout mice in vivo

Evidence Level

Not specified

Key Findings

1
Knockdown or peptide inhibition of RTN4R, the gene encoding the RTN4/NoGo-Receptor, lowers ataxin-2 protein levels in mouse and human neurons in vitro.
2
Rtn4r knockout mice exhibit reduced ataxin-2 levels in vivo, indicating that RTN4/NoGo-Receptor is necessary to maintain ataxin-2 levels in the nervous system.
3
Knockdown of ataxin-2 promotes axonal regeneration in primary cortical neurons following injury, suggesting a role for ataxin-2 in limiting regeneration after nerve injury.

Research Summary

The study performs a genome-wide siRNA screen to identify RTN4R 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 vitro, and Rtn4r knockout mice have reduced ataxin-2 levels in vivo. The 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.

Practical Implications

Therapeutic Target for ALS/SCA2

The RTN4/NoGo-Receptor is identified as a potential therapeutic target for reducing ataxin-2 levels in ALS and SCA2.

Nerve Injury Treatment

Targeting ataxin-2 could be a potential treatment following nerve injury due to its role in limiting axonal regeneration.

Combination Therapies

The identification of additional targets and strategies to lower ataxin-2 allows for envisioning combination therapies to maximize therapeutic benefit.

Study Limitations

1
The effectiveness of RTN4R knockdown in rescuing degeneration in a mouse model of ALS remains to be tested.
2
The precise method for reducing RTN4R—and subsequently ATXN2—in mouse models to test its influence on disease phenotypes needs further determination.
3
The data presented should not be considered as preclinical but rather as new directions to build upon for modulating ataxin-2 that require further validation.

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