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

被引：20

作者：

Dachsel, Justus C. ^{[1
]}

Nishioka, Kenya ^{[1
]}

Vilarino-Gueell, Carles ^{[1
]}

Lincoln, Sarah J. ^{[1
]}

Soto-Ortolaza, Alexandra I. ^{[1
]}

Kachergus, Jennifer ^{[1
]}

Hinkle, Kelly M. ^{[1
]}

Heckman, Michael G. ^{[3
]}

Jasinska-Myga, Barbara ^{[1
]}

Taylor, Julie P. ^{[1
]}

Dickson, Dennis W. ^{[2
]}

Gibson, Rachel A. ^{[4
]}

Hentati, Faycal ^{[5
]}

Ross, Owen A. ^{[1
]}

Farrer, Matthew J. ^{[1
]}

机构：

[1] Mayo Clin, Dept Neurosci, Div Neurogenet, Jacksonville, FL 32224 USA

[2] Mayo Clin, Dept Pathol, Jacksonville, FL 32224 USA

[3] Mayo Clin, Coll Med, Biostat Unit, Jacksonville, FL 32224 USA

[4] GlaxoSmithKline, Res & Dev, Harlow, Essex, England

[5] Inst Natl Neurol, Serv Neurol, Tunis, Tunisia

来源：

MECHANISMS OF AGEING AND DEVELOPMENT | 2010年 / 131卷 / 03期

关键词：

LRRK2; PD; Dimerization; Genetics; p.G2019S; KINASE-ACTIVITY; LRRK2; LEUCINE-RICH-REPEAT-KINASE-2; PENETRANCE; VARIANTS; DOMAIN; GENE; ROC;

D O I：

10.1016/j.mad.2010.01.009

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

引用

页码：210 / 214

页数：5

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