Table 2 Examples of genes associated with PD risk

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 [70,71,72]

• Risk variants likely increase LRRK2 activity [70,71,72]

• 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 [77,78,79,80]

• 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]