Combined kinase inhibition modulates parkin inactivation.
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 (PD). Although its precise function remains largely unknown, parkin seems to play a neuroprotective role. Several studies indicate that changes in parkin solubility induced by post-translational 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 PD, but the role of this post-translational 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 PD 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 PD.
Rubio de la Torre
Elena
E
Institute of Parasitology and Biomedicine López-Neyra, Consejo Superior de Investigaciones Científicas, Granada, Spain.
Luzón-Toro
Berta
B
Forte-Lago
Irene
I
Minguez-Castellanos
Adolfo
A
Ferrer
Isidro
I
Hilfiker
Sabine
S
D001921:Brain / Q000378:metabolism; D047389:Casein Kinase I / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D006801:Humans; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D047389:Casein Kinase I; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human