ALS-associated genes in SCA2 mouse spinal cord transcriptomes
Daniel R Scoles1, Warunee Dansithong1, Lance T Pflieger1,2
1Department of Neurology, University of Utah, 175 North Medical Drive East, 5th Floor, Salt Lake City, UT 84132, USA.
Abstract:
The spinocerebellar ataxia type 2 (SCA2) gene ATXN2 has a prominent role in the pathogenesis and treatment of amyotrophic lateral sclerosis (ALS). In addition to cerebellar ataxia, motor neuron disease is often seen in SCA2, and ATXN2 CAG repeat expansions in the long normal range increase ALS risk. Also, lowering ATXN2 expression in TDP-43 ALS mice prolongs their survival. Here we investigated the ATXN2 relationship with motor neuron dysfunction in vivo by comparing spinal cord (SC) transcriptomes reported from TDP-43 and SOD1 ALS mice and ALS patients with those from SCA2 mice. SC transcriptomes were determined using an SCA2 bacterial artificial chromosome mouse model expressing polyglutamine expanded ATXN2. SCA2 cerebellar transcriptomes were also determined, and we also investigated the modification of gene expression following treatment of SCA2 mice with an antisense oligonucleotide (ASO) lowering ATXN2 expression. Differentially expressed genes (DEGs) defined three interconnected pathways (innate immunity, fatty acid biosynthesis and cholesterol biosynthesis) in separate modules identified by weighted gene co-expression network analysis. Other key pathways included the complement system and lysosome/phagosome pathways. Of all DEGs in SC, 12.6% were also dysregulated in the cerebellum. Treatment of mice with an ATXN2 ASO also modified innate immunity, the complement system and lysosome/phagosome pathways. This study provides new insights into the underlying molecular basis of SCA2 SC phenotypes and demonstrates annotated pathways shared with TDP-43 and SOD1 ALS mice and ALS patients. It also emphasizes the importance of ATXN2 in motor neuron degeneration and confirms ATXN2 as a therapeutic target.
Insights
The ATXN2 gene is crucial in spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS). Lowering ATXN2 expression in SCA2 mice impacts motor neuron pathways, confirming ATXN2 as a therapeutic target for ALS.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- The ATXN2 gene is implicated in spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS) pathogenesis.
- Expanded CAG repeats in ATXN2 are linked to increased ALS risk and motor neuron disease in SCA2 patients.
- Reducing ATXN2 expression shows therapeutic potential in mouse models of ALS.
Purpose of the Study:
- To investigate the role of ATXN2 in motor neuron dysfunction in vivo.
- To compare spinal cord transcriptomes of SCA2 mice with those of other ALS models and patients.
- To explore the effects of ATXN2-lowering antisense oligonucleotide (ASO) treatment in SCA2 mice.
Main Methods:
- Utilized an SCA2 bacterial artificial chromosome mouse model with polyglutamine-expanded ATXN2.
- Performed spinal cord and cerebellar transcriptome analysis.
- Applied weighted gene co-expression network analysis to identify key pathways.
- Assessed gene expression changes after ATXN2 ASO treatment.
Main Results:
- Identified three interconnected pathways (innate immunity, fatty acid, and cholesterol biosynthesis) dysregulated in SCA2 spinal cords.
- Found significant overlap in differentially expressed genes between spinal cord and cerebellum.
- Observed that ATXN2 ASO treatment modulated innate immunity, complement, and lysosome/phagosome pathways.
- Demonstrated shared molecular pathways between SCA2, TDP-43, and SOD1 ALS models.
Conclusions:
- Provides novel insights into the molecular mechanisms underlying SCA2 spinal cord phenotypes.
- Highlights the conserved role of ATXN2 in motor neuron degeneration across different ALS subtypes.
- Confirms ATXN2 as a promising therapeutic target for ALS treatment.
