@article{8d98710a3eb94f42bdbd1d4234efbfc8,
title = "Heterodimerization of Lrrk1-Lrrk2: Implications for LRRK2-associated Parkinson disease",
abstract = "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.",
keywords = "Dimerization, Genetics, LRRK2, P.G2019S, PD",
author = "Dachsel, {Justus C.} and Kenya Nishioka and Carles Vilari{\~n}o-G{\"u}ell and Lincoln, {Sarah J.} and Soto-Ortolaza, {Alexandra I.} and Jennifer Kachergus and Hinkle, {Kelly M.} and Heckman, {Michael G.} and Barbara Jasinska-Myga and Taylor, {Julie P.} and Dickson, {Dennis W.} and Gibson, {Rachel A.} and Faycal Hentati and Ross, {Owen A.} and Farrer, {Matthew J.}",
note = "Funding Information: The authors wish to thank the patients and families who participated in the study. Special thanks to Drs Jina Swartz, Ray Watts, and David Burns for the neurological expertise provided during study design and for their clinical input. We are indebted to the contributions of Lefkos T. Middleton MD, Mounir Kefi MD, Lianna Ishihara-Paul PhD, Rim Amouri PhD, Samia Ben Yahmed MD, Samia Ben Sassi MD, Mourad Zouari MD, Ghada El Euch MD. GlaxoSmithKline financially supported the patient recruitment and clinical data collection. Statistical analysis was supported by the Neurogenetic Core of a Morris K. Udall Center, National Institute of Neurological Disorders and Stroke P50 NS40256. MJF and FH were supported in part by NIH grant R21 NS64885 . KN was supported by an Eli-Lilly scholarship and Herb Geist gift for Lewy body research. ",
year = "2010",
month = mar,
doi = "10.1016/j.mad.2010.01.009",
language = "English (US)",
volume = "131",
pages = "210--214",
journal = "Mechanisms of Ageing and Development",
issn = "0047-6374",
publisher = "Elsevier Ireland Ltd",
number = "3",
}