Background: Mutations in LRRK2 are associated with familial and sporadic Parkinson’s disease (PD). Subjects with PD caused by LRRK2 mutations show pleiotropic pathology that can involve inclusions containing α-synuclein, tau or neither protein. The mechanisms by which mutations in LRRK2 lead to this pleiotropic pathology remain unknown. Objectives: To investigate mechanisms by which LRRK2 might cause PD. Methods: We used systems biology to investigate the transcriptomes from human brains, human blood cells and Caenorhabditis elegans expressing wild-type LRRK2. The role of autophagy was tested in lines of C. elegans expressing LRRK2, V337M tau or both proteins. Neuronal function was measured by quantifying thrashing. Results: Genes regulating autophagy were coordinately regulated with LRRK2. C. elegans expressing V337M tau showed reduced thrashing, as has been noted previously. Coexpressing mutant LRRK2 (R1441C or G2019S) with V337M tau increased the motor deficits. Treating the lines of C. elegans with an mTOR inhibitor that enhances autophagic flux, ridaforolimus, increased the thrashing behavior to the same level as nontransgenic nematodes. Conclusion: These data support a role for LRRK2 in autophagy, raise the possibility that deficits in autophagy contribute to the pathophysiology of LRRK2, and point to a potential therapeutic approach addressing the pathophysiology of LRRK2 in PD.
© 2011 S. Karger AG, Basel
- LRRK2 mutations
- Familial and sporadic Parkinson’s disease
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Benjamin Wolozin, MD, PhD
Departments of Pharmacology and Neurology
Boston University School of Medicine
72 East Concord St., R614, Boston, MA 02118-2526 (USA)
Tel. +1 617 414 2652, E-Mail firstname.lastname@example.org
Received: July 11, 2011
Accepted after revision: August 25, 2011
Published online: December 23, 2011
Number of Print Pages : 4
Number of Figures : 1, Number of Tables : 0, Number of References : 17
Vol. 10, No. 1-4, Year 2012 (Cover Date: April 2012)
Journal Editor: Nitsch R.M. (Zürich), Hock C. (Zürich)
ISSN: 1660-2854 (Print), eISSN: 1660-2862 (Online)
For additional information: http://www.karger.com/NDD
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