Cerebellar Micro-RNA Profile in a Mouse Model of Spinocerebellar Ataxia Type 2

Sharan Paul; Warunee Dansithong; Mandi Gandelman; Karla P Figueroa; Daniel R Scoles; Stefan M Pulst

doi:10.1212/NXG.0000000000200144

Cerebellar Micro-RNA Profile in a Mouse Model of Spinocerebellar Ataxia Type 2

Neurol Genet. 2024 Mar 28;10(2):e200144. doi: 10.1212/NXG.0000000000200144. eCollection 2024 Apr.

Authors

Sharan Paul¹, Warunee Dansithong¹, Mandi Gandelman¹, Karla P Figueroa¹, Daniel R Scoles¹, Stefan M Pulst¹

Affiliation

¹ From the Department of Neurology, University of Utah.

Abstract

Background and objectives: Micro-RNAs (miRNAs) are critical for regulating the expression of genes in multiple neurodegenerative diseases, but miRNAs have not been investigated in spinocerebellar ataxia type 2 (SCA2). SCA2, a dominantly inherited progressive neurodegenerative polyglutamine (polyQ) disease, is caused by a CAG repeat expansion in the ataxin-2 (ATXN2) gene. In this study, we determined miRNA transcriptomes in SCA2-BAC-ATXN2[Q72] transgenic mice.

Methods: We assessed the expression of miRNAs in SCA2 transgenic mouse cerebella using the HiSeq Illumina sequencer. We used the miRNA target filter tool in Qiagen Ingenuity Pathway Analysis (IPA) to identify target genes of differentially expressed miRNAs (DEmiRs) within in the SCA2 mouse transcriptomes and then performed pathway analyses.

Results: Our analysis revealed significant changes in the expression levels of multiple miRNAs in mice with SCA2. We identified 81 DEmiRs in mice with SCA2, with 52 miRNAs upregulated and 29 miRNAs downregulated after onset of rotarod deficit. Subsequent IPA processing enabled us to establish connections between these DEmiRs and specific biological regulatory functions. Furthermore, by using the IPA miRNA target filter, we identified target genes of DEmiRs in the SCA2-BAC-ATXN2[Q72] transcriptome data set and demonstrated their significant impact on several biological functional and disease pathways.

Discussion: Our study establishes the role of both DEmiRs and their targets in SCA2 pathogenesis. By expressing mutant ATXN2 under the control of its endogenous regulatory elements in the SCA2-BAC-ATXN2[Q72] mouse model, we identified a set of DEmiRs that are shared across multiple neurodegenerative diseases including other SCAs, Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS). There was a significant overlap of both DEmiRs and their targets of BAC-ATXN2[Q72] transcriptomes in dysregulated pathways that characterize SCA2. This observation also extended to dysregulated pathways in ALS, AD, and PD. DEmiRs identified in this study may represent therapeutic targets for neurodegeneration or lead to biomarkers for characterizing various neurodegenerative diseases.