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The Journal of Neuroscience, October 1, 2008, 28(40):10090-10101; doi:10.1523/JNEUROSCI.3237-08.2008

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Neurobiology of Disease
Dopaminergic and Glutamatergic Signaling Crosstalk in Huntington's Disease Neurodegeneration: The Role of p25/Cyclin-Dependent Kinase 5

Paola Paoletti,^1,2 Ingrid Vila,^1,2 Maria Rifé,^1,2 José Miguel Lizcano,³ Jordi Alberch,^1,2 and Silvia Ginés^1,2

¹Departament de Biologia Cellular, Immunologia i Neurociències, Facultat de Medicina, Institut d'Investigacions Biomèdiques August Pi i Sunyer and ²Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Universitat de Barcelona, E-08036 Barcelona, Spain, and ³Institut de Neurociències i Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, E-08193 Barcelona, Spain

Correspondence should be addressed to Silvia Ginés, Universitat de Barcelona, Casanova 143, E-08036 Barcelona, Spain. Email: silviagines{at}ub.edu

Altered glutamatergic and dopaminergic signaling has been proposed as contributing to the specific striatal cell death observed in Huntington's disease (HD). However, the precise mechanisms by which mutant huntingtin sensitize striatal cells to dopamine and glutamate inputs remain unclear. Here, we demonstrate in knock-in HD striatal cells that mutant huntingtin enhances dopamine-mediated striatal cell death via dopamine D₁ receptors. Moreover, we show that NMDA receptors specifically potentiate the vulnerability of mutant huntingtin striatal cells to dopamine toxicity as pretreatment with NMDA increased D₁R-induced cell death in mutant but not wild-type cells. As potential underlying mechanism of increased striatal vulnerability, we identified aberrant cyclin-dependent kinase 5 (Cdk5) activation. We demonstrate that enhanced Cdk5 phosphorylation and increased calpain-mediated conversion of the Cdk5 activator p35 into p25 may account for the deregulation of Cdk5 associated to dopamine and glutamate receptor activation in knock-in HD striatal cells. Moreover, supporting a detrimental role of Cdk5 in striatal cell death, neuronal loss can be widely prevented by roscovitine, a potent Cdk5 inhibitor. Significantly, reduced Cdk5 expression together with enhanced Cdk5 phosphorylation and p25 accumulation also occurs in the striatum of mutant Hdh^Q111 mice and HD human brain suggesting the relevance of deregulated Cdk5 pathway in HD pathology. These findings provide new insights into the molecular mechanisms underlying the selective vulnerability of striatal cells in HD and identify p25/Cdk5 as an important mediator of dopamine and glutamate neurotoxicity associated to HD.

Key words: striatum; neurotoxicity; huntingtin; dopamine D₁ receptors; glutamate; p25

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Received July 10, 2008; accepted Aug. 18, 2008.

Correspondence should be addressed to Silvia Ginés, Universitat de Barcelona, Casanova 143, E-08036 Barcelona, Spain. Email: silviagines{at}ub.edu

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