Objective: To uncover early pathogenic events occurring prior to neuronal loss and Lewy body formation in human PD brain.

Background: In PD, pathological changes spread throughout the brain in a predictable spatiotemporal sequence. Early stage PD cases exhibit a gradient of pathology from unaffected to severe, thus enabling a comparison to be made between pathologically affected regions with pathologically unaffected regions predicted to develop PD pathology later in the disease. This may allow us to capture the earliest molecular changes that represent potentially primary events in the pathogenesis of sporadic disease.

Methods: Braak stage 3/4 cases and controls were matched for age, post-mortem delay and pH. Microdissection from 8 Braak stage regions (Substantia nigra, caudate, putamen, temporal cortex, parahippocampus, cingulate cortex, frontal cortex, parietal cortex) and the cerebellum was performed, yielding a total of 66 control and 66 samples. Proteins were extracted, digested and expression changes investigated using quantitative label-free mass spectrometry based proteomics. Quantitative validation was performed using multiple reaction monitoring and functional validation was performed using mitochondrial respiratory chain assays.

Results: Our method provided an in-depth coverage of the human brain proteome, detecting 1147 unique proteins. A GO analysis highlighted significant and frequently affected biological processes in PD brain were mitochondrial, including mitochondrial metabolism, ATP synthesis, respiratory chain function and TCA cycle. Next we selected proteins that changed in >4 PD affected brain regions, with significant fold changes in at least one brain region. 39% of the top candidate proteins were mitochondrial located proteins. Targeted proteomics validated a subset of proteins that changed significantly in areas of mild or no pathology.

Conclusions: The application of mass-spectrometry based proteomics and targeted proteomics to a unique collection of early stage Parkinson’s disease cases highlighted that mitochondrial processes are altered in both unaffected and affected regions in PD. Such changes are detected prior to the development of Lewy body pathology and may suggest that mitochondrial dysfunction is an early pathogenic process in sporadic PD.

Preliminary data presented at British Neuropathological Society 2015.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/detailed-proteomic-analysis-of-early-pd-brain-highlights-altered-expression-of-mitochondrial-proteins-as-an-important-event-in-sporadic-pd/