Molecular genetics of Parkinson's disease: Contributions and global trends

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder primarily characterized by motor dysfunction. Aging is the greatest risk factor for developing PD. Recent molecular genetic studies have revealed that genetic factors, in addition to aging and environmental factors, play an important role in the development of the disorder. Studies of familial PD have identified approximately 20 different causative genes. PRKN is the most frequently detected causative gene in Japan. The PRKN gene is located at a common fragile site, and both copy number variants as well as single nucleotide variants are frequently detected. The location and variety of variant types makes an accurate genetic diagnosis difficult with conventional genetic testing. In sporadic PD, genome-wide association studies have revealed more than 200 genes that are potential drivers for the development of PD. Many of these studies have been conducted in Caucasian populations alone, which has limited the identification of all genetic risk factors for sporadic PD, particularly as genetic backgrounds vary widely by race. The Global Parkinson's Genetics Program is a global undertaking meant to address the issue of regional differences in genetic studies of PD.

Fig. 1

Strategies to identify genetic factors in PD and applications of the findings. The search for genes associated with PD relies on the molecular genetic characteristics of PD patients and the classification of samples into familial PD and sporadic PD groups. After PD-associated genes are discovered, cellular and animal PD models are used to reveal pathophysiological functions and for precision medicine applications

Fig. 2

Pseudo-heterozygotes in the PRKN gene. Copy number variations tested by qPCR showed that the PD patient (green) had a heterozygous duplication in exons 6–7. The PD patient inherited a duplication of exons 3–7 from the father (blue) and a deletion of exons 3–5 from the mother (orange), resulting in compound heterozygous variants in the PRKN gene

Fig. 3

RNAseq analysis of autosomal recessive juvenile parkinsonism (ARJP) patients with PRKN single heterozygous variants. RNAseq analysis of five ARJP patients (right half) and five controls (left half) shows one example of a gene whose expression is prominently and significantly downregulated only in ARJP patients