TY - JOUR
T1 - Combined kinase inhibition modulates parkin inactivation
AU - de la Torre, Elena Rubio
AU - Luzón-Toro, Berta
AU - Forte-Lago, Irene
AU - Minguez-Castellanos, Adolfo
AU - Ferrer, Isidro
AU - Hilfiker, Sabine
N1 - Funding Information: This work was supported by grants from the Fondo de Inves-tigación Sanitaria (FIS-PI040262), the Fundación Ramón Areces and the Junta de Andalucia. S.H. was supported by a Ramón y Cajal Fellowship. Funding to Pay the Open Access Charge was provided by a grant from the Spanish Ministry of Science and Innovation (BFU2007-63635).
PY - 2009
Y1 - 2009
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/60549088301
UR - https://www.scopus.com/pages/publications/60549088301#tab=citedBy
U2 - 10.1093/hmg/ddn407
DO - 10.1093/hmg/ddn407
M3 - Article
C2 - 19050041
SN - 0964-6906
VL - 18
SP - 809
EP - 823
JO - Human molecular genetics
JF - Human molecular genetics
IS - 5
ER -