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The Journal of Neuroscience, October 31, 2007, 27(44):11865-11868; doi:10.1523/JNEUROSCI.3695-07.2007

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Symposia and Mini-Symposia
The Roles of Kinases in Familial Parkinson's Disease

Mark R. Cookson,¹ William Dauer,² Ted Dawson,³ Edward A. Fon,⁴ Ming Guo,⁵ and Jie Shen⁶

¹Cell Biology and Gene Expression Unit, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland 20892-3707, ²Departments of Neurology and Pharmacology, Columbia University, New York, New York 10032, ³The Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, ⁴Center for Neuronal Survival, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada H3A 2B4, ⁵Department of Neurology, Brain Research Institute, University of California, Los Angeles School of Medicine, Los Angeles, California 90095, and ⁶Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115

Correspondence should be addressed to Dr. Mark Cookson, Building 35/Porter Building, 1A116, 35 Convent Drive, Bethesda, MD 20892. Email: cookson{at}mail.nih.gov

The purpose of this mini-symposium is to discuss some of the inherited forms of Parkinson's disease (PD) in view of recent data suggesting that some of the proteins affect cellular signaling pathways. As an illustration, we shall focus on two different kinases associated with recessive and dominant forms of PD. Mutations in the mitochondrial kinase PTEN (phosphatase and tensin homolog)-induced kinase 1 (PINK1) are loss-of-function mutations in a normally neuroprotective protein. Loss-of-function mutations in model organisms have variable effects, from dramatic muscle and spermatid defects in Drosophila to more subtle neurophysiological abnormalities in mice. Several lines of evidence relate these to the action of a second gene for familial PD, parkin, an E3 ubiquitin ligase shown recently to have effects on Akt signaling. Mutations in leucine-rich repeat kinase 2 (LRRK2), a cytosolic kinase, are dominant and have the opposite effect of causing neuronal damage. The mechanism(s) involved are uncertain at this time because LRRK2 is a large and complex molecule with several domains. Increased kinase activity accounts for the action of at least some of the mutations, suggesting that hyperactive or misregulated kinase activity may lead to the damaging effects of LRRK2 in neurons. For both PINK1 and LRRK2, the following key question that needs to be answered: what are the physiological substrates that mediate effects in cells? Here, we will discuss some of the recent thinking about physiological and pathological roles for signaling in PD and how these may have therapeutic implications for the future.

Key words: Parkinson's disease; dopaminergic; genetics; human; knock-out mice; mitochondria; neuron death; phosphorylation; protein kinases; signal transduction

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Received Aug. 14, 2007; accepted Aug. 20, 2007.

Correspondence should be addressed to Dr. Mark Cookson, Building 35/Porter Building, 1A116, 35 Convent Drive, Bethesda, MD 20892. Email: cookson{at}mail.nih.gov

This article has been cited by other articles:

				E. Rubio de la Torre, B. Luzon-Toro, I. Forte-Lago, A. Minguez-Castellanos, I. Ferrer, and S. Hilfiker Combined kinase inhibition modulates parkin inactivation Hum. Mol. Genet., March 1, 2009; 18(5): 809 - 823. [Abstract] [Full Text] [PDF]

				Z. Liu, X. Wang, Y. Yu, X. Li, T. Wang, H. Jiang, Q. Ren, Y. Jiao, A. Sawa, T. Moran, et al. A Drosophila model for LRRK2-linked parkinsonism PNAS, February 19, 2008; 105(7): 2693 - 2698. [Abstract] [Full Text] [PDF]

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