Autosomal-dominant missense mutations in LRRK2 (leucine-rich repeat kinase 2) are a common genetic cause of PD (Parkinson's disease). LRRK2 is a multidomain protein with kinase and GTPase activities. Dominant mutations are found in the domains that have these two enzyme activities, including the common G2019S mutation that increases kinase activity 2–3-fold. However, there is also a genetic variant in some populations, G2385R, that lies in a C-terminal WD40 domain of LRRK2 and acts as a risk factor for PD. In the present study we show that the G2385R mutation causes a partial loss of the kinase function of LRRK2 and deletion of the C-terminus completely abolishes kinase activity. This effect is strong enough to overcome the kinase-activating effects of the G2019S mutation in the kinase domain. Hsp90 (heat-shock protein of 90 kDa) has an increased affinity for the G2385R variant compared with WT (wild-type) LRRK2, and inhibition of the chaperone binding combined with proteasome inhibition leads to association of mutant LRRK2 with high molecular mass native fractions that probably represent proteasome degradation pathways. The loss-of-function of G2385R correlates with several cellular phenotypes that have been proposed to be kinase-dependent. These results suggest that the C-terminus of LRRK2 plays an important role in maintaining enzymatic function of the protein and that G2385R may be associated with PD in a way that is different from kinase-activating mutations. These results may be important in understanding the differing mechanism(s) by which mutations in LRRK2 act and may also have implications for therapeutic strategies for PD.
Skip Nav Destination
Article navigation
August 2012
-
Cover Image
Cover Image
- PDF Icon PDF LinkFront Matter
- PDF Icon PDF LinkTable of Contents
- PDF Icon PDF LinkEditorial Board
Research Article|
July 27 2012
The G2385R variant of leucine-rich repeat kinase 2 associated with Parkinson's disease is a partial loss-of-function mutation
Iakov N. Rudenko;
Iakov N. Rudenko
*Cell Biology and Gene Expression Section, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, U.S.A.
Search for other works by this author on:
Alice Kaganovich;
Alice Kaganovich
*Cell Biology and Gene Expression Section, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, U.S.A.
Search for other works by this author on:
David N. Hauser;
David N. Hauser
*Cell Biology and Gene Expression Section, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, U.S.A.
†Brown University/National Institutes of Health Graduate Partnership Program, Department of Neuroscience, Brown University, Providence, RI 02912, U.S.A.
Search for other works by this author on:
Aleksandra Beylina;
Aleksandra Beylina
*Cell Biology and Gene Expression Section, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, U.S.A.
Search for other works by this author on:
Ruth Chia;
Ruth Chia
*Cell Biology and Gene Expression Section, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, U.S.A.
Search for other works by this author on:
Jinhui Ding;
Jinhui Ding
‡Bioinformatics Facility, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892
Search for other works by this author on:
Dragan Maric;
Dragan Maric
§Flow Cytometry Core Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, U.S.A.
Search for other works by this author on:
Howard Jaffe;
Howard Jaffe
∥Peptide Sequencing Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, U.S.A.
Search for other works by this author on:
Mark R. Cookson
Mark R. Cookson
1
*Cell Biology and Gene Expression Section, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, U.S.A.
1To whom correspondence should be addressed (email cookson@mail.nih.gov).
Search for other works by this author on:
Publisher: Portland Press Ltd
Received:
April 16 2012
Revision Received:
May 19 2012
Accepted:
May 22 2012
Accepted Manuscript online:
May 22 2012
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem J (2012) 446 (1): 99–111.
Article history
Received:
April 16 2012
Revision Received:
May 19 2012
Accepted:
May 22 2012
Accepted Manuscript online:
May 22 2012
Citation
Iakov N. Rudenko, Alice Kaganovich, David N. Hauser, Aleksandra Beylina, Ruth Chia, Jinhui Ding, Dragan Maric, Howard Jaffe, Mark R. Cookson; The G2385R variant of leucine-rich repeat kinase 2 associated with Parkinson's disease is a partial loss-of-function mutation. Biochem J 15 August 2012; 446 (1): 99–111. doi: https://doi.org/10.1042/BJ20120637
Download citation file:
Sign in
Don't already have an account? Register
Sign in to your personal account
You could not be signed in. Please check your email address / username and password and try again.
Could not validate captcha. Please try again.