Table 2.

Examples of genes associated with PD risk

Gene	Prevalence in PD	Proposed pathogenic mechanisms	Therapeutic strategies
SNCA (PARK1) [53]	• Missense and multiplication mutations are rare and cause monogenic familial PD [59] • Common polymorphisms are risk factors for sporadic PD [64, 66]	• Missense mutations are located in N-terminal region of α-synuclein and cause a variety of structural effects: formation of oligomeric aggregates, loss of membrane binding [67] • Duplications, triplications and common polymorphisms increase α-synuclein expression [56, 57]	• Decrease α-synuclein production and aggregation [68] • Increase α-synuclein degradation by activating autophagy [68] • Decrease extracellular α-synuclein e.g. using α-synuclein antibodies [68] • Inhibit uptake of extracellular α-synuclein [68]
LRRK2 (PARK8) [69]	• Present in 40% of familial cases and 10% of sporadic cases [65]	• Monogenic pathogenic mutations either reduce GTPase activity or increases kinase activity [70–72] • Risk variants likely increase LRRK2 activity [70–72]	• LRRK2 kinase inhibitors [73, 74]
GBA [75, 76]	• Prevalence varies with ethnicity but is as high as 30% in Ashkenazi Jews and 10% in Chinese and Japanese [77–80]	• Reduction in GCase activity results in accumulation of substrates (e.g. glucosylceramide) and of α-synuclein [81]	• Small molecule chaperones to increase GCase activity [68] • Substrate reduction e.g. glucosylceramide synthase inhibitors [68]