Spinocerebellar Ataxia Type 2 (SCA2) Spinal Cord Transcriptome Sequencing Informs Understanding on ALS (S18.005)

Objective: The objective of this study is to characterize the spinal cord (SC) transcriptome of spinocerebellar ataxia type 2 (SCA2) mice, and to characterize SC genes modified by ATXN2 ASO treatment. Background: CAG repeat expansions in the ATXN2 gene are the cause of SCA2 and increase the risk of amyotrophic lateral sclerosis (ALS). Patients with SCA2 also often present with motor neuron disease characteristic of ALS. Our past work demonstrated that lowering the expression of ATXN2 using an antisense oligonucleotide (ASO) delivered to the lateral ventricle improved motor, molecular and neurophysiological phenotypes of two different SCA2 mouse models. In addition, reduction of Atxn2 expression genetically or by ASO improved the survival of TDP-43 ALS mice. Design/Methods: RNA-seq of SC and cerebellar (CB) RNAs was performed using BAC-ATXN2-Q72 mice vs wildtype littermates, including comparison of ASO vs saline treatments (total N=28). Differentially expressed genes (DEGs) were analyzed by weighted gene co-expression network analysis (WGCNA), and pathway analysis (GO, KEGG, IPA). Results: The DEG cutoff used was P 0.585. 12.6% of DEGs were shared between SC and CB. WGCNA identified three SC gene modules significantly correlated with SCA2. Top pathways of each were immune system processes, lipid/cholesterol biosynthesis, and ion transport. DEGs in the spinal cord of SCA2 mice treated with ATXN2 ASO vs saline associated with lysosome/phagosome functions. Modulation of these pathways by the disease-modifying ASO aligns with new data we have on abnormal autophagy in SCA2. We also identified DEGs related to ALS in SCA2 mouse SC, including reduced Slc1a2 expression, mutated in ALS. Conclusions: This study provides new insights into the underlying molecular basis of ALS motor neuron phenotypes observed in SCA2, and possible therapeutic targets for ALS given that reduction of ATXN2 increased TDP-43 ALS mouse survival. Study Supported by: Supported by NIH grants R21NS081182, R01NS097903, and R37NS033123. Disclosure: Dr. Scoles has nothing to disclose. Dr. Dansithong has nothing to disclose. Dr. Pflieger has nothing to disclose. Dr. Paul has nothing to disclose. Dr. Figueroa has nothing to disclose. Dr. Schneider has nothing to disclose. Dr. Rigo has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis pharmaceuticals. Dr. Bennett has nothing to disclose. Dr. Pulst has nothing to disclose.