Genetic insights into sporadic Parkinson's disease pathogenesis

Abstract

Intensive research over the last 15 years has led to the identification of several autosomal recessive and dominant genes that cause familial Parkinson's disease (PD). Importantly, the functional characterization of these genes has shed considerable insights into the molecular mechanisms underlying the etiology and pathogenesis of PD. Collectively; these studies implicate aberrant protein and mitochondrial homeostasis as key contributors to the development of PD, with oxidative stress likely acting as an important nexus between the two pathogenic events. Interestingly, recent genome-wide association studies (GWAS) have revealed variations in at least two of the identified familial PD genes (i.e. α-synuclein and LRRK2) as significant risk factors for the development of sporadic PD. At the same time, the studies also uncovered variability in novel alleles that is associated with increased risk for the disease. Additionally, in-silico meta-analyses of GWAS data have allowed major steps into the investigation of the roles of gene-gene and gene-environment interactions in sporadic PD. The emergent picture from the progress made thus far is that the etiology of sporadic PD is multi-factorial and presumably involves a complex interplay between a multitude of gene networks and the environment. Nonetheless, the biochemical pathways underlying familial and sporadic forms of PD are likely to be shared.

Keywords: Alpha-synuclein; DJ-1; GWAS; LRRK2; Mitophagy.; PINK1; Parkin; Protein aggregation.

Fig. (1)

Autosomal dominant PD-linked genes. Schematic depiction of the protein structure of α-synuclein and LRRK2 showing the various domains and the location of disease-associated missense mutations - including the G2385R “Asian risk variant” for LRRK2. (NAC, Nonamyloid component; ANK, Ankyrin-like repeats; LRR, Leucine-rich repeats; ROC, Ras of complex proteins - a GTPase domain; CPR, Cterminal of ROC).

Fig. (2)

Autosomal recessive PD-linked genes. Schematic depiction of the protein structure of parkin and PINK1 showing the various domains and the location of disease-associated mutations. (UBL, Ubiquitin-like domain; RING, Really Interesting New Gene domain; IBR, Inbetween RING domain; MTS, Mitochondrial targeting sequence).