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.
Dachsel
Justus C
JC
Division of Neurogenetics, Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA. daechsel.justus@mayo.edu
Nishioka
Kenya
K
Vilariño-Güell
Carles
C
Lincoln
Sarah J
SJ
Soto-Ortolaza
Alexandra I
AI
Kachergus
Jennifer
J
Hinkle
Kelly M
KM
Heckman
Michael G
MG
Jasinska-Myga
Barbara
B
Taylor
Julie P
JP
Dickson
Dennis W
DW
Gibson
Rachel A
RA
Hentati
Faycal
F
Ross
Owen A
OA
Farrer
Matthew J
MJ
D017668:Age of Onset; D006801:Humans; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics*; D020734:Parkinsonian Disorders / Q000235:genetics*; D019683:Penetrance; D055503:Protein Multimerization / Q000235:genetics*