- LRRK2 mutations
- Familial and sporadic Parkinson’s disease
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.
Copyright © 2011 S. Karger AG, Basel
- Greggio E, Cookson MR: Leucine-rich repeat kinase 2 mutations and Parkinson’s disease: three questions. ASN Neuro 2009;1(pii):e00002.
- West AB, Moore DJ, Biskup S, Bugayenko A, Smith WW, Ross CA, Dawson VL, Dawson TM: Parkinson’s disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc Natl Acad Sci USA 2005;102:16842–16847.
- West AB, Moore DJ, Choi C, Andrabi SA, Li X, Dikeman D, Biskup S, Zhang Z, Lim KL, Dawson VL, Dawson TM: Parkinson’s disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity. Hum Mol Genet 2007;16:223–232.
- Greggio E, Jain S, Kingsbury A, Bandopadhyay R, Lewis P, Kaganovich A, van der Brug MP, Beilina A, Blackinton J, Thomas KJ, Ahmad R, Miller DW, Kesavapany S, Singleton A, Lees A, Harvey RJ, Harvey K, Cookson MR: Kinase activity is required for the toxic effects of mutant LRRK2/dardarin. Neurobiol Dis 2006;23:329–341.
- Lewis PA, Greggio E, Beilina A, Jain S, Baker A, Cookson MR: The R1441C mutation of LRRK2 disrupts GTP hydrolysis. Biochem Biophys Res Commun 2007;357:668–671.
- Xiong Y, Coombes CE, Kilaru A, Li X, Gitler AD, Bowers WJ, Dawson VL, Dawson TM, Moore DJ: GTPase activity plays a key role in the pathobiology of LRRK2. PLoS Genet 2010;6:e1000902.
- Greggio E, Zambrano I, Kaganovich A, Beilina A, Taymans JM, Daniels V, Lewis P, Jain S, Ding J, Syed A, Thomas KJ, Baekelandt V, Cookson MR: The Parkinson disease-associated leucine-rich repeat kinase 2 (LRRK2) is a dimer that undergoes intramolecular autophosphorylation. J Biol Chem 2008;283:16906–16914.
- Berger Z, Smith KA, Lavoie MJ: Membrane localization of LRRK2 is associated with increased formation of the highly active LRRK2 dimer and changes in its phosphorylation. Biochemistry 2010;49:5511–5523.
- Chan D, Citro A, Cordy JM, Shen GC, Wolozin B: Rac1 protein rescues neurite retraction caused by G2019S leucine-rich repeat kinase 2 (LRRK2). J Biol Chem 2011;286:16140–16149.
- Gehrke S, Imai Y, Sokol N, Lu B: Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression. Nature 2010;466:637–641.
- Plowey ED, Cherra SJ 3rd, Liu YJ, Chu CT: Role of autophagy in G2019S-LRRK2-associated neurite shortening in differentiated SH-SY5Y cells. J Neurochem 2008;105:1048–1056.
- Saha S, Guillily MD, Ferree A, Lanceta J, Chan D, Ghosh J, Hsu CH, Segal L, Raghavan K, Matsumoto K, Hisamoto N, Kuwahara T, Iwatsubo T, Moore L, Goldstein L, Cookson M, Wolozin B: LRRK2 modulates vulnerability to mitochondrial dysfunction in Caenorhabditis elegans. J Neurosci 2009;29:9210–9218.
- Faith JJ, Hayete B, Thaden JT, Mogno I, Wierzbowski J, Cottarel G, Kasif S, Collins JJ, Gardner TS: Large-scale mapping and validation of Escherichia coli transcriptional regulation from a compendium of expression profiles. PLoS Biol 2007;5:e8.
- di Bernardo D, Thompson MJ, Gardner TS, Chobot SE, Eastwood EL, Wojtovich AP, Elliott SJ, Schaus SE, Collins JJ: Chemogenomic profiling on a genome-wide scale using reverse-engineered gene networks. Nat Biotechnol 2005;23:377–383.
- Guillily M, Li H, Latourelle JC, Pyenson N, Richter L, Raghavan G, Saha S, Dusonchet J, Lee-Armandt JP, Glicksman M, Yue Z, Myers RH, Collins JJ, Wolozin G: A reverse engineered Parkinson’s disease gene regulatory network identifies RGS2 as a direct modulator of LRRK2 activity. Submitted.
- Kraemer BC, Zhang B, Leverenz JB, Thomas JH, Trojanowski JQ, Schellenberg GD: Neurodegeneration and defective neurotransmission in a Caenorhabditis elegans model of tauopathy. Proc Natl Acad Sci USA 2003;100:9980–9985.
- Rivera VM, Squillace RM, Miller D, Berk L, Wardwell SD, Ning Y, Pollock R, Narasimhan NI, Iuliucci JD, Wang F, Clackson T: Ridaforolimus (AP23573; MK-8669), a potent mTOR inhibitor, has broad antitumor activity and can be optimally administered using intermittent dosing regimens. Mol Cancer Ther 2011;10:1059–1071.
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)
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