Objective: The identification of early disease markers for Parkinson’s disease (PD) is essential, since the disease is already in an advanced state when motor symptoms become obvious. Large-scale omics data analysis from animal models may help to identify perturbations in molecular pathways before histological or behavioural changes appear. Thus, identifying early disease-related mechanisms can facilitate the development of human biomarkers and new therapeutic approaches.

Background: To enable a disease-specific analysis of perturbed molecular pathways from omics data, we have compiled a significant amount of literature-based knowledge (>1000 PMID) on PD into a molecular interaction map. This “PD map” is a constantly updated, freely accessible knowledge repository (http://pdmap.uni.lu), enabling the upload of omics data and interpretation in a PD-related cellular context.

Methods: Ventral midbrain (containing Substantia Nigra (SN)) from transgenic mice moderately overexpressing E46-mutated alpha-synuclein (about 1.5x over endogenous) was prepared from 3, 9 and 13 months-old animals. This mouse line shows mild PD-like pathology (e.g. striatal TH deficits) starting at 9 months of age, but no loss of SN tyrosine-hydroxylase positive neurons. RNA was prepared and analysed on Affymetrix whole-transcript expression arrays. Differentially expressed genes were uploaded to the PD map and displayed within the molecular network.

Results: Data from the 3 months-old age group showed a distinct under-expression of genes (e.g., TH, DDC, DAT, VMAT2) related to dopamine metabolism and secretion. In addition an over-expression of genes involved in receptor mediated calcium signalling was detected. Interestingly, no motor symptoms, loss of TH positive neurons or striking alpha-synuclein aggregations were visible at this early age.

Conclusions: Gene expression analysis using the PD map highlights early molecular changes in the ventral midbrain of alpha-synuclein over-expressing mice. Direct perturbation of dopamine and calcium signalling related cellular pathways by alpha-synuclein, e.g., through interaction with upstream transcription factors such as NR4A2, might be a key mechanism in early PD pathogenesis, independent of high–molecular, aggregated alpha-synuclein.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/gene-expression-analysis-using-the-parkinsons-disease-map-reveals-early-effects-of-alpha-synuclein-on-pd-pathogenesis/