Parkinson's Disease (PD) is a complex neurodegenerative disorder that affects nearly 1 in every 500 people and can be either idiopathic, acquired or hereditary.
Genetic research has identified six distinct chromosomal regions containing genes with mutations that conclusively cause monogenic PD, where a mutation in a single gene is sufficient to cause the phenotype.
- The SNCA gene encodes an abundant 140-amino acid cytosolic protein, a-synuclein. Missense SNCA mutations cause PD through a toxic gain of function.
- LRRK2 gene mutations are the most frequent known cause of late-onset autosomal dominant and sporadic PD, but the pathogenic mechanisms are still unclear.
- PARK2 is the second largest gene in human genome and the 465-amino acid Parkin protein functions as an E3 ubiquitin ligase in the process of ubiquitination.
- PINK1 encodes a ubiquitously expressed protein kinase, which targets mitochondria. The majority of reported mutations in PINK1 are loss-of-function mutations affecting the kinase domain.
- PARK7 is ubiquitously expressed and functions as a cellular sensor of oxidative stress, but mutations linked to PD show reduced neuro-protective function and antioxidant activity.
- The ATP13A2 protein is a lysosomal membrane protein, and most mutations are truncated and unstable and so are retained and degraded in the endoplasmic reticulum.
In addition to these, several genes may be new targets for treatment by either turning on (TOMM7 and HSPA1L) or off (BAG4) gene activity.