Human Molecular Genetics Advance Access published online on December 2, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn407
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Combined kinase inhibition modulates parkin inactivation
1 Institute of Parasitology and Biomedicine "López-Neyra", Consejo Superior de Investigaciones Científicas (CSIC), Granada, Spain 2 Department of Neurology, Virgen de las Nieves University Hospital, Granada, Spain 3 Institute of Neuropathology, IDIBELL-University Hospital Bellvitge, University of Barcelona, Llobregat, Spain
* Corresponding author: Tel: +34 958 18 16 54; Fax: +34 958 18 16 32; e-mail: sabine.hilfiker{at}ipb.csic.es
Received October 3, 2008; Revised November 30, 2008; Accepted November 30, 2008
Mutations in the parkin gene cause autosomal recessive, juvenile-onset parkinsonism, and parkin dysfunction may also play a role in the pathogenesis of sporadic Parkinson disease. Whilst its precise function remains largely unknown, parkin seems to play a neuroprotective role. Several studies indicate that changes in parkin solubility induced by posttranslational modifications, such as S-nitrosylation or dopamine modification, comprise one mechanism of parkin inactivation associated with disease. Protein phosphorylation events have recently been linked to the molecular mechanism(s) underlying Parkinson disease, but the role of this posttranslational modification for parkin function has remained unclear. Here we report that compound phosphorylation of parkin by both casein kinase I and cyclin-dependent kinase 5 (cdk5) decreases parkin solubility, leading to its aggregation and inactivation. Combined kinase inhibition partially reverses the aggregative properties of several pathogenic point mutants in cultured cells. Enhanced parkin phosphorylation is detected in distinct brain areas of individuals with sporadic Parkinson disease, and correlates with increases in the levels of p25, the activator of cdk5. These findings indicate that casein kinase I and cdk5 may represent novel combinatorial therapeutic targets for treating Parkinson disease.