Calpain-regulated p35/cdk5 plays a central role in dopaminergic neuron death through modulation of the transcription factor myocyte enhancer factor 2.
The mechanisms underlying dopamine neuron loss in Parkinson's disease (PD) are not clearly defined. Here, we delineate a pathway by which dopaminergic loss induced by 1-methyl-4-phenyl 1,2,3,6 tetrahydropyridine (MPTP) is controlled in vivo. We reported previously that calpains play a central required role in dopamine loss after MPTP treatment. Here, we provide evidence that the downstream effector pathway of calpains is through cyclin-dependent kinase 5 (cdk5)-mediated modulation of the transcription factor myocyte enhancer factor 2 (MEF2). We show that MPTP-induced conversion of the cdk5 activator p35 to a pathogenic p25 form is dependent on calpain activity in vivo. In addition, p35 deficiency attenuates MPTP-induced dopamine neuron loss and behavioral outcome. Moreover, MEF2 is phosphorylated on Ser444, an inactivating site, after MPTP treatment. This phosphorylation is dependent on both calpain and p35 activity, consistent with the model that calpain-mediated activation of cdk5 results in phosphorylation of MEF2 in vivo. Finally, we provide evidence that MEF2 is critical for dopaminergic loss because "cdk5 phosphorylation site mutant" of MEF2D provides neuroprotection in an MPTP mouse model of PD. Together, these data indicate that calpain-p35-p25/cdk5-mediated inactivation of MEF2 plays a critical role in dopaminergic loss in vivo.
Smith
Patrice D
PD
Ottawa Health Research Institute, Ottawa, Ontario, K1H 8M5, Canada.
Mount
Matthew P
MP
Shree
Raj
R
Callaghan
Steve
S
Slack
Ruth S
RS
Anisman
Hymie
H
Vincent
Inez
I
Wang
Xuemin
X
Mao
Zixu
Z
Park
David S
DS
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000502:physiology; D002154:Calpain / Q000502:physiology*; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology; D051360:Cyclin-Dependent Kinase 5 / Q000502:physiology*; D004298:Dopamine / Q000032:analysis*; D004789:Enzyme Activation; D064326:MEF2 Transcription Factors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009474:Neurons / Q000737:chemistry / Q000473:pathology*; D020734:Parkinsonian Disorders / Q000378:metabolism*; D010766:Phosphorylation; D017354:Point Mutation; D011499:Protein Processing, Post-Translational; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology
D002135:Calcium-Binding Proteins; D064326:MEF2 Transcription Factors; C578041:Mef2c protein, mouse; C578044:Mef2d protein, mouse; D018006:Myogenic Regulatory Factors; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; C089495:neuronal Cdk5 activator (p25-p35); C033668:calpastatin; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; D002154:Calpain; D004298:Dopamine