Heterodimerization of Lrrk1–Lrrk2: Implications for LRRK2-associated Parkinson disease

LRRK2 mutations are recognized as the most frequent genetic cause of both familial and sporadic parkinsonism identified to date. A remarkable feature of this form of parkinsonism is the variable penetrance of symptom manifestation resulting in a wide range of age-at-onset in patients. Herein we use a functional approach to identify the Lrrk1 protein as a potential disease modifier demonstrating an interaction and heterodimer formation with Lrrk2. In addition, evaluation of LRRK1 variants in our large Lrrk2 p.G2019S-parkinsonism series from a Tunisian (n = 145) identified a missense mutation (p.L416M) resulting in an average 6.2 years younger age at disease onset. In conclusion we show that the interaction of Lrrk1–Lrrk2 can form protein dimers and this interaction may influence the age of symptomatic manifestation in Lrrk2-parkinsonism patients.