Abstract
Spinocerebellar ataxia type 2 (SCA2) is a polyglutamine disorder, and variants in its disease protein Ataxin-2 act as modifiers in the progression of Amyotrophic Lateral Sclerosis. There are no reliable molecular biomarkers for SCA2. The aim of this study was to define novel molecular biomarker candidates for SCA2. Using cerebellar and cervicothoracic spinal cord RNA/protein from Atxn2-CAG100-KnockIn (KIN) and wildtype mice, a multi-omics study was conducted based on the integration of global transcriptomic, proteomic, and phosphoproteomic data, followed by validation in mice and humans. Venn diagram comparisons across all OMICS datasets indicated that only Serpinb1a-transcript, SERPINB1A-protein and -phosphopeptides were consistently downregulated at terminal stage in 14-month-old KIN mice. Expression studies in cerebellum and spinal cord from 10 weeks (pre-manifest), 6-month-old (early ataxic), and 14-month-old (late ataxic stage) mice confirmed this progressive decrease at mRNA and protein level. SERPINB1 plasma levels were significantly lower in early-stage SCA2 patients, and displayed a significant association with the CAG repeat length at expanded ATXN2 alleles, the age at onset and INAS count. However, these human data from this SCA2 founder population were not robust, so reappraisal in large international studies and at later disease stages of SCA2 is needed. SERPINB1 was identified as novel candidate progression biomarker for SCA2 pathomechanisms.