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.

Pygmy MicroRNA: Surveillance Cops in Therapy Kingdom

“…Herpes simplex virus 1 (HSV1)-encoded miRNA, miR-LAT, targets pro-apoptotic transforming growth factor β (TGFβ) and SMAD3, thereby inhibiting apoptosis of latently infected neurons (116,117). Host cells also use miRNA to regulate replication of viruses; for example, host cell-encoded miR-32 inhibits replication (hAgo2) may lead to misregulation of many miRs (59,61,96). This is also associated with other neurodegenerative diseases such as Huntington's disease, ataxia, epilepsy, traumatic injury (97), Tourette's syndrome, neuropsychiatric diseases such as schizophrenia, and amyotrophic lateral sclerosis (ALS) (98-100).…”

Flies with Parkinson's disease

“…Interestingly, numerous connections between sporadic and familial forms of the disease exist: eg causative genes to PD are misregulated in sporadic forms of the disease (e.g. Parkin or LRRK2 (Chai and Lim, 2013;Lesage and Brice, 2012)), or typical protein aggregates that are often seen in sporadic and familial cases of the disease (Lewy bodies) are enriched in alpha-synuclein, a protein that is also found mutated in some familial forms (Spillantini et al, 1997).…”

Commentary: Identification of potential therapeutic compounds for Parkinson's disease using Drosophila and human cell models

“…As mentioned above, most PD cases are sporadic; however, several genes involved in rare familial forms of the disease appear to be affected in sporadic PD 3 . It has been shown that causative genes to PD like parkin or LRRK2 are misregulated in sporadic PD cases 44,45 . Regarding the DJ-1 gene, previous studies have demonstrated that the DJ-1 protein is oxidatively modified, and probably inactivated, in sporadic PD cases 46 .…”