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The Journal of Neuroscience, March 26, 2008, 28(13):3384-3391; doi:10.1523/JNEUROSCI.0185-08.2008

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Neurobiology of Disease
The Chaperone Activity of Heat Shock Protein 90 Is Critical for Maintaining the Stability of Leucine-Rich Repeat Kinase 2

Lizhen Wang,¹ Chengsong Xie,¹ Elisa Greggio,² Loukia Parisiadou,¹ Hoon Shim,¹ Lixin Sun,¹ Jayanth Chandran,¹ Xian Lin,¹ Chen Lai,¹ Wan-Jou Yang,¹ Darren J. Moore,^3,4 Ted M. Dawson,^3,4,5 Valina L. Dawson,^3,4,5 Gabriela Chiosis,⁶ Mark R. Cookson,² and Huaibin Cai¹

Units of ¹Transgenesis and ²Cell Biology and Gene Expression, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland 20892, ³Institute for Cell Engineering, Departments of ⁴Neurology and ⁵Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21025, and ⁶Program in Molecular Pharmacology and Chemistry, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021

Correspondence should be addressed to Huaibin Cai, Unit of Transgenesis, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Building 35, Room 1A116, MSC 3707, 35 Convent Drive, Bethesda, MD 20892-3707. Email: caih{at}mail.nih.gov

Parkinson's disease (PD), a progressive neurodegenerative disease characterized by bradykinesia, rigidity, and resting tremor, is the most common neurodegenerative movement disorder. Although the majority of PD cases are sporadic, some are inherited, including those caused by leucine-rich repeat kinase 2 (LRRK2) mutations. The substitution of serine for glycine at position 2019 (G2019S) in the kinase domain of LRRK2 represents the most prevalent genetic mutation in both familial and apparently sporadic cases of PD. Because mutations in LRRK2 are likely associated with a toxic gain of function, destabilization of LRRK2 may be a novel way to limit its detrimental effects. Here we show that LRRK2 forms a complex with heat shock protein 90 (Hsp90) in vivo and that inhibition of Hsp90 disrupts the association of Hsp90 with LRRK2 and leads to proteasomal degradation of LRRK2. Hsp90 inhibitors may therefore limit the mutant LRRK2-elicited toxicity to neurons. As a proof of principle, we show that Hsp90 inhibitors rescue the axon growth retardation caused by overexpression of the LRRK2 G2019S mutation in neurons. Therefore, inhibition of LRRK2 kinase activity can be achieved by blocking Hsp90-mediated chaperone activity and Hsp90 inhibitors may serve as potential anti-PD drugs.

Key words: Hsp90; LRRK2; G2019S; Parkinson's disease; protein degradation; chaperone

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Received Nov. 21, 2007; revised Feb. 13, 2008; accepted Feb. 13, 2008.

Correspondence should be addressed to Huaibin Cai, Unit of Transgenesis, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Building 35, Room 1A116, MSC 3707, 35 Convent Drive, Bethesda, MD 20892-3707. Email: caih{at}mail.nih.gov

Related articles in J. Neurosci.:

Heat Shock Protein 90 Modulates LRRK2 Stability: Potential Implications for Parkinson's Disease Treatment

Andrés Hurtado-Lorenzo and Vasanti S. Anand
J. Neurosci. 2008 28: 6757-6759. [Full Text]  

This article has been cited by other articles:

				H. S. Ko, R. Bailey, W. W. Smith, Z. Liu, J.-H. Shin, Y.-I. Lee, Y.-J. Zhang, H. Jiang, C. A. Ross, D. J. Moore, et al. CHIP regulates leucine-rich repeat kinase-2 ubiquitination, degradation, and toxicity PNAS, February 24, 2009; 106(8): 2897 - 2902. [Abstract] [Full Text] [PDF]

				A. Hurtado-Lorenzo and V. S. Anand Heat Shock Protein 90 Modulates LRRK2 Stability: Potential Implications for Parkinson's Disease Treatment J. Neurosci., July 2, 2008; 28(27): 6757 - 6759. [Full Text] [PDF]

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