Dopaminergic and glutamatergic signaling crosstalk in Huntington's disease neurodegeneration : the role of p25/cyclin-dependent kinase 5
Paoletti, Paola (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Vila, Ingrid (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Rifé, Maria (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Lizcano de Vega, José Miguel (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Alberch i Vié, Jordi (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Ginés, Silvia (Institut d'Investigacions Biomèdiques August Pi i Sunyer)

Data:	2008
Resum:	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 dopaminemediated striatal cell death via dopamineD1 receptors. Moreover, we show thatNMDAreceptors specifically potentiate the vulnerability of mutant huntingtin striatal cells to dopamine toxicity as pretreatment withNMDAincreased 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 HdhQ111 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.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials i que es distribueixin sota la mateixa llicència que regula l'obra original. Cal que es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Striatum ; Neurotoxicity ; Huntingtin ; Dopamine D ; Glutamate ; P25 ; Estriat ; Neurotoxicitat ; Huntingtina ; Dopamina D ; Glutamat
Publicat a:	The Journal of neuroscience, Vol. 28 No. 40 (Oct. 2008) , p. 10090-10101, ISSN 1529-2401

DOI: 10.1523/JNEUROSCI.3237-08.2008
PMID: 18829967

12 p, 4.7 MB

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