Molecular mechanisms defining penetrance ofLRRK2-associated Parkinson’s disease

Abstract Mutations inLeucine-rich repeat kinase 2(LRRK2) are the most frequent cause of dominantly inherited Parkinson’s disease (PD).LRRK2mutations, among which p.G2019S is the most frequent, are inherited with reduced penetrance. Interestingly, the disease risk associated withLRRK2G2019S can vary dramatically depending on the ethnic background of the carrier. While this would suggest a genetic component in the definition ofLRRK2-PD penetrance, only few variants have been shown to modify the age at onset of patients harbouringLRRK2mutations, and the exact cellular pathways controlling the transition from a healthy to a diseased state currently remain elusive. In light of this knowledge gap, recent studies also explored environmental and lifestyle factors as potential modifiers ofLRRK2-PD. In this article, we (i) describe the clinical characteristics ofLRRK2mutation carriers, (ii) review known genes linked toLRRK2-PD onset and (iii) summarize the cellular functions ofLRRK2with particular emphasis on potential penetrance-related molecular mechanisms. This section coversLRRK2’s involvement in Rab GTPase and immune signalling as well as in the regulation of mitochondrial homeostasis and dynamics. Additionally, we explored the literature with regard to (iv) lifestyle and (v) environmental factors that may influence the penetrance ofLRRK2mutations, with a view towards further exposomics studies. Finally, based on this comprehensive overview, we propose potential futurein vivo,in vitroandin silicostudies that could provide a better understanding of the processes triggering PD in individuals withLRRK2mutations.