Brain-wide transcriptome-based metabolic alterations in Parkinsons disease: human inter-region and human-experimental model correlations

Alterations in brain metabolism are closely associated with the molecular hallmarks of Parkinsons disease (PD). A clear understanding of the main metabolic perturbations in PD is therefore important. Here, we retrospectively analysed the expression of metabolic genes from 34 PD-control post-mortem human brain transcriptome data from literature, spanning multiple brain regions, and found significant metabolic correlations between the Substantia nigra (SN) and cerebral cortical tissues with high perturbations in protein modification, transport, nucleotide and inositol phosphate metabolic pathways. Moreover, three main metabolic clusters of SN tissues were identified from patient cohort studies, each characterised by perturbations in (a) pyruvate, amino acid, neurotransmitter, and complex lipid metabolisms (b) inflammation-related metabolism, and (c) lipid breakdown for energy metabolism. Finally, we analysed 58 PD-control transcriptome data from in vivo/in vitro disease models and identified experimental PD models with significant correlations to matched human brain regions. Collectively, our findings are based on 47 PD transcriptome datasets covering 92 PD-control comparisons spanning more than 1000 samples in total, and they suggest metabolic alterations in several brain regions, heterogeneity in metabolic alterations between study cohorts for the SN tissues and suggest the need to optimize current experimental models to advance research on metabolic aspects of PD.