Systems-based analyses of brain regions functionally impacted in Parkinson's disease reveals underlying causal mechanisms

Detailed analysis of disease-affected tissue provides insight into molecular mechanisms contributing to pathogenesis. Substantia nigra, striatum and cortex are functionally connected with increasing degreesof alpha-synuclein pathology in Parkinson's disease. Functional and causal pathway analysis of gene expression and proteomic alterations in these three regions revealed pathways that correlated with depositionof alpha-synuclein. Microarray and RNAseq experiments revealed previously unidentified causal changes related to oligodendrocyte function and synaptic vesicle release and other changes were reflected acrossall brain regions. Importantly a subset of these changes were replicated in Parkinson's disease blood. Proteomic assessment revealed alterations in mitochondria and vesicular transport proteins that preceded genegene expression changes indicating defects in translation and/or protein turnover. Our combined approach of proteomics, RNAseq and microarray analyses provides a comprehensive view of the molecular changesthat accompany alpha-synculein pathology in Parkinson's disease, and may be instrumental in understanding and diagnosing Parkinson's disease progression.

keywords: NCBI GEO expression profiling by array