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 degrees of alpha-synuclein pathology in Parkinson's disease. We undertook functional and causal pathway analysis of gene expression and proteomic alterations in these three regions, and the data revealed pathways that correlated with disease progression. In addition, microarray and RNAseq experiments revealed previously unidentified causal changes related to oligodendrocyte function and synaptic vesicle release, and these and other changes were reflected across all brain regions. Importantly, subsets of these changes were replicated in Parkinson's disease blood; suggesting peripheral tissue may provide important avenues for understanding and measuring disease status and progression. Proteomic assessment revealed alterations in mitochondria and vesicular transport proteins that preceded gene 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 changes that accompany functional loss and alpha-synuclein pathology in Parkinson's disease, and may be instrumental to understand, diagnose and follow Parkinson's disease progression.

Pure akinesia as initial presentation of PSP: a clinicopathological study.

Pure akinesia (PA) is a rare neurodegenerative condition that may represent a limited expression of progressive supranuclear palsy (PSP). Only a few pathological studies have been reported and its classification remains unclear. We report the case of a 57-year-old Caucasian man who was initially clinically diagnosed with classical PA. After four years the patient developed additional symptoms and signs compatible with the diagnosis of clinically probable PSP. The diagnosis of PSP was confirmed by post-mortem examination. Genetic analysis of the MAPT gene revealed an A0/A0 genotype, which has been repeatedly associated with the PSP phenotype, and might discriminate between PA and other gait disorders. Our case strengthens the hypothesis that PA should be considered as initial manifestation of PSP.