Systems-Based Analyses of Brain Regions Functionally Impacted in Parkinson's Disease Reveals Underlying Causal Mechanisms

Abstract

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.

Deregulation of protein translation control, a potential game-changing hypothesis for Parkinson's disease pathogenesis

“…Indeed, eIF2a phosphorylation is reported to be increased in PD and is closely associated with aggregates of a-synuclein, indicating ER stress induced by misfolded proteins and increased protein translation through the unfolded protein response [35,36]. In addition, a recent study combining transcriptomics and proteomics of three PD related brain regions (substantia nigra, striatum, and frontal cortex) to compare health and disease states shows a subset of protein abundance changes largely independent of mRNA changes [37]. The study indicated that protein expression regulation mechanisms are active in PD.…”

How close are we to revealing the etiology of Parkinson's disease?

“…Disorders of calcium homeostasis, excitotoxicity from increased glutamatergic input and neuroinflammation are other factors. Many interactions between these and other noxious factors are well documented [1,13,15]. Disturbed calcium homeostasis, abnormal cortical metabolism and other molecular changes due to the convergence of multiple deficits have been observed in early stages of PD [16].…”

“…Disturbed calcium homeostasis, abnormal cortical metabolism and other molecular changes due to the convergence of multiple deficits have been observed in early stages of PD [16]. Overwhelming evidence has emerged showing that deposition of misfolded aSyn and its oligomers in the cytoplasm of selected neuronal populations, as well as their interaction with other proteins, particularly in their oligomeric forms, which might synergistically promote their mutual aggregation and vice versa, play a critical role in amplifying neuronal damage [1,2,13,15]. However, the basic mechanisms leading to the intimate association and synergism of these proteins, suggesting a dualism or triad of amyloidogenic neurodegeneratiom await further clarification.…”

“…Cell-to-cell transfer of aSyn can explain the formation of Lewy bodies and neurites, but may not account for the full spectrum of PD including the involvement of multiple non-dopaminergic neuronal populations, although correlations exist between the degrees of neuronal degeneration in some of them [1]. Mounting evidence implicates that aSyn interacts with other proteins and propagates neurodegeneration by a transneuronal spread, which may provide an acceptable explanation for the stereotypic distribution of Lewy pathology in PD [1,15,19,20]. However, the causes of formation of neurotoxic soluble and oligomeric species of aSyn and other noxious proteins, the exact mechanisms underlying the prion-like spread and the contribution of aSyn and other self-propagating proteins in the development and propagation of PD require further elucidation.…”

Network and Pathway-Based Analyses of Genes Associated with Parkinson’s Disease

“…Previously, Parkinson's disease was thought to be caused primarily by environmental factors, but research is revealing that the disease develops from a complicated interplay of genetic and environmental factors [8]. In the last decade, a number of studies have contributed a lot to our understanding of the pathological and molecular mechanisms of PD, from the perspective of animal models [9][10][11], gene expression [12][13][14][15], genome-wide association (GWA) studies [16][17][18][19], and systems biology [20][21][22][23][24]. The identification of the possible essential proteins such as leucine-rich repeat kinase 2 (LRRK2), PTEN-induced putative kinase 1 (PINK1), parkin (PARK2), PARK7, ubiquitin carboxyl-terminal esterase L1 (UCHL1), glucocerebrosidase (GBA), and alpha-synuclein (SNCA) has significantly accelerated the process of understanding its molecular causes.…”