Molecular mechanisms defining penetrance of -associated Parkinson's disease.

Mutations in () are the most frequent cause of dominantly inherited Parkinson's disease (PD). mutations, among which p.G2019S is the most frequent, are inherited with reduced penetrance. Interestingly, the disease risk associated with G2019S can vary dramatically depending on the ethnic background of the carrier. While this would suggest a genetic component in the definition of -PD penetrance, only few variants have been shown to modify the age at onset of patients harbouring mutations, 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 of -PD. In this article, we (i) describe the clinical characteristics of mutation carriers, (ii) review known genes linked to -PD onset and (iii) summarize the cellular functions of with particular emphasis on potential penetrance-related molecular mechanisms. This section covers '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 of mutations, with a view towards further exposomics studies. Finally, based on this comprehensive overview, we propose potential future , and studies that could provide a better understanding of the processes triggering PD in individuals with mutations.