BioProject

Ataxin-2 (ATXN2) polyglutamine domain expansions of large size result in an autosomal dominantly inherited multi-system-atrophy of the nervous system named Spinocerebellar ataxia type 2 (SCA2), while expansions of intermediate size act as polygenic risk factors for levodopa-responsive Parkinson’s disease (PD) and for motor neuron disease (ALS and FTLD). More...

Ataxin-2 (ATXN2) polyglutamine domain expansions of large size result in an autosomal dominantly inherited multi-system-atrophy of the nervous system named Spinocerebellar ataxia type 2 (SCA2), while expansions of intermediate size act as polygenic risk factors for levodopa-responsive Parkinson’s disease (PD) and for motor neuron disease (ALS and FTLD). In view of the established role of ATXN2 for RNA processing and the expression of ATXN2 in blood cells such as platelets, we investigated whether global deep RNA sequencing of whole blood from SCA2 patients identifies a molecular profile which might serve as diagnostic biomarker. The bioinformatic analysis of the SCA2 blood transcriptome revealed various significant effects, prominently on the pathways of Huntington’s disease and PD where mitochondrial dysfunction is crucial. Notably, an induction of PINK1 and PARK7 expression was observed. Conversely, PINK1 expression was severely decreased upon global transcriptome profiling of Atxn2-knockout mouse cerebellum and liver, in parallel to strong effects on OPA1 and GHITM, which encode known mitochondrial dynamics regulators. These results were validated by quantitative PCR and immunoblots. ATXN2 expression was induced by nutrient deprivation of human SH-SY5Y neuroblastoma cells, with a time course in parallel to PINK1 expression, and PINK1 levels appeared to depend on ATXN2 knockdown. Thus, ATXN2 may be upstream of or parallel to PINK1 in mitochondrial quality control and autophagy. Given that PINK1 is responsible for autosomal recessive juvenile Parkinson’s disease (PD), this genetic interaction offers an explanation how the degeneration of nigrostriatal dopaminergic neurons and the Parkinson phenotype are triggered by ATXN2 mutations. Less...