Genes Implicated in Familial Parkinson's Disease Provide a Dual Picture of Nigral Dopaminergic Neurodegeneration with Mitochondria Taking Center Stage

Abstract

The mechanism of nigral dopaminergic neuronal degeneration in Parkinson's disease (PD) is unknown. One of the pathological characteristics of the disease is the deposition of α-synuclein (α-syn) that occurs in the brain from both familial and sporadic PD patients. This paper constitutes a narrative review that takes advantage of information related to genes (SNCA, LRRK2, GBA, UCHL1, VPS35, PRKN, PINK1, ATP13A2, PLA2G6, DNAJC6, SYNJ1, DJ-1/PARK7 and FBXO7) involved in familial cases of Parkinson's disease (PD) to explore their usefulness in deciphering the origin of dopaminergic denervation in many types of PD. Direct or functional interactions between genes or gene products are evaluated using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. The rationale is to propose a map of the interactions between SNCA, the gene encoding for α-syn that aggregates in PD, and other genes, the mutations of which lead to early-onset PD. The map contrasts with the findings obtained using animal models that are the knockout of one of those genes or that express the mutated human gene. From combining in silico data from STRING-based assays with in vitro and in vivo data in transgenic animals, two likely mechanisms appeared: (i) the processing of native α-syn is altered due to the mutation of genes involved in vesicular trafficking and protein processing, or (ii) α-syn mutants alter the mechanisms necessary for the correct vesicular trafficking and protein processing. Mitochondria are a common denominator since both mechanisms require extra energy production, and the energy for the survival of neurons is obtained mainly from the complete oxidation of glucose. Dopamine itself can result in an additional burden to the mitochondria of dopaminergic neurons because its handling produces free radicals. Drugs acting on G protein-coupled receptors (GPCRs) in the mitochondria of neurons may hopefully end up targeting those receptors to reduce oxidative burden and increase mitochondrial performance. In summary, the analysis of the data of genes related to familial PD provides relevant information on the etiology of sporadic cases and might suggest new therapeutic approaches.

Keywords: Lewy bodies; early-onset Parkinson’s disease; familial Parkinson’s disease; mitochondria; mitophagy; synuclein aggregation; vesicular transport.

Figure 1

STRING analysis of connections between (human) genes in Table 1. Panel (A): using by default settings. Panel (B). Restricted settings (mainly leaving aside connections driven by PD-related literature; see text for details). Panel (C): Interaction-enriched connection pattern (see text for details). Line color code: sky blue, known interactions from curated databases; magenta, experimentally determined interactions; green, predicted from neighborhood; red, predicted from gene fusions; blue, predicted from gene co-occurrence; pastel green, textmining; black, coexpression; and clear violet, protein homology.

Figure 2

Enriched STRING analysis of connections between (human) genes in Table 1. Line color code; sky blue, known interactions from curated databases; magenta, experimentally determined interactions; green, predicted from neighborhood; red, predicted from gene fusions; blue, predicted from gene co-occurrence; pastel green, textmining; black, coexpression; and clear violet, protein homology.

Figure 3

Mechanisms of dyshomeostasis of dopaminergic neurons. Panel (A). Mutations in SNCA leads to aggregation of mutated α-synuclein that affects the mechanisms of protein handling and vesicle transport, thus dysbalancing mitochondrial dynamics and function. Panel (B). Mutations in genes that affect protein processing, vesicle transport and mitochondrial function leads to aggregation of non-mutated α-synuclein. Red dots represent ATP molecules, mainly synthesized in the mitochondria of neurons, that are needed for all the processes depicted in the schemes.