Parkinson's disease: From genetics to molecular dysfunction and targeted therapeutic approaches

Abstract

Parkinson's disease (PD) is the most common neurodegenerative movement disorder in the elderly. As the pathogenesis of PD is still not fully understood, medications with the capacity of halting the disease progression are currently unavailable. The discovery of genes that are causative for, or increase susceptibility to PD is pivotal for the development of novel therapeutic approaches, as they are critical for the onset of PD and the molecular pathways underlying its pathogenesis. By reviewing relevant data, we discuss causative genes, and those associated with PD susceptibility and quantitative traits. Through Gene Ontology database and STRING analysis, we emphasize the roles of inorganic cation transmembrane transport pathways and hypothalamic pituitary thyroid axis, in addition to the established roles of inflammation/oxidative stress and mitochondrial dysfunction in the pathogenesis of PD. It is hoped these insights 1) untangle the clinical complex presentations of PD, 2) reveal the interwoven molecular network leading to PD, and 3) identify critical molecular targets to facilitate novel PD drug discovery, with a view to providing improved consultation and personalized medicine for patients with PD in the future.

Keywords: Drug discovery; Genetics; Molecular function; Parkinson's disease; Quantitative traits.

Figure 1

Bar chart of different categories of the protein functions. The proteins are encoded by the PD risk genes and their functions base on Gene Ontology (GO) database. The bar chart is stimulated using Metascape. The top 25 of the function categories were included in this chart.

Figure 2

Network diagram demonstrates interactions between the risk gene products. The PD risk genetic products network shows 105 nodes and 111 edges. The different colours in the figure indicate different biological processes in which the highlighted genes are involved. Red represents “regulation of peroxidase activity”; Dark blue represents “activated T cell proliferation”; Light green represents “glycosylceramide catabolic process”; Light yellow represents “negative regulation of protein targeting to mitochondrion”; Pink represents “negative regulation of establishment of protein localization to mitochondrion”; Dark green represents “positive regulation of nitric-oxide synthase biosynthetic process”; Light blue represents “negative regulation of amine transport”; Dark yellow represents “response to thyroid hormone”; Purple represents “negative regulation of response to drug”; Brown represents “regulation of cytokine production involved in inflammatory response”. The graphic is made using STRING v11.0.