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Targeting RTN4/NoGo-Receptor reduces levels of ALS protein ataxin-2
Caitlin M Rodriguez1, Sophia C Bechek1, Graham L Jones2
1Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
Abstract:
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.
Insights
Researchers identified the RTN4/NoGo-Receptor as a novel target to reduce ataxin-2 levels. Lowering ataxin-2 may treat neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxia type 2 (SCA2).
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Emerging gene-based therapies aim to reduce ataxin-2 levels for neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxia type 2 (SCA2).
- Additional therapeutic strategies to lower ataxin-2 are needed.
Purpose of the Study:
- To identify novel targets for reducing ataxin-2 levels.
- To explore the therapeutic potential of targeting RTN4R for neurological disorders.
Main Methods:
- Genome-wide arrayed small interfering RNA (siRNA) screen in human cells.
- Validation of RTN4R knockdown and peptide inhibition in mouse and human neurons.
- Analysis of Rtn4r knockout mice.
- Assessment of axonal regeneration following axotomy.
Main Results:
- RTN4R (encoding RTN4/NoGo-Receptor) was identified as a potent modifier of ataxin-2 levels.
- RTN4R knockdown and peptide inhibition reduced ataxin-2 levels in vitro.
- Rtn4r knockout mice exhibited lower ataxin-2 levels in vivo.
- Ataxin-2 and RTN4/NoGo-Receptor share a role in limiting axonal regeneration; reducing either protein enhanced axonal regrowth.
Conclusions:
- RTN4/NoGo-Receptor is a novel therapeutic target for amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxia type 2 (SCA2).
- Targeting ataxin-2 may be a potential treatment strategy for nerve injury and regeneration.
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