Cyclin-dependent kinase 5 is a mediator of dopaminergic neuron loss in a mouse model of Parkinson's disease.
Recent evidence indicates that cyclin-dependent kinases (CDKs, cdks) may be inappropriately activated in several neurodegenerative conditions. Here, we report that cdk5 expression and activity are elevated after administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a toxin that damages the nigrostriatal dopaminergic pathway. Supporting the pathogenic significance of the cdk5 alterations are the findings that the general cdk inhibitor, flavopiridol, or expression of dominant-negative cdk5, and to a lesser extent dominant-negative cdk2, attenuates the loss of dopaminergic neurons caused by MPTP. In addition, CDK inhibition strategies attenuate MPTP-induced hypolocomotion and markers of striatal function independent of striatal dopamine. We propose that cdk5 is a key regulator in the degeneration of dopaminergic neurons in Parkinson's disease.
Smith
Patrice D
PD
Neuroscience Group, Ottawa Health Research Institute, Ottawa, ON, Canada K1H 8M5.
Crocker
Stephen J
SJ
Jackson-Lewis
Vernice
V
Jordan-Sciutto
Kelly L
KL
Hayley
Shawn
S
Mount
Matthew P
MP
O'Hare
Michael J
MJ
Callaghan
Steven
S
Slack
Ruth S
RS
Przedborski
Serge
S
Anisman
Hymie
H
Park
David S
DS
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D002851:Chromatography, High Pressure Liquid; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000378:metabolism / Q000502:physiology*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005799:Genes, Dominant; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D010300:Parkinson Disease / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology; D013997:Time Factors
D015259:Dopamine Agents; D005419:Flavonoids; D010880:Piperidines; C077990:alvocidib; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; D018844:Cyclin-Dependent Kinases; D004298:Dopamine