CDK4 and CDK5 inhibition imitates cold exposure in the prevention of mitochondrial fission and neuron death after MPP+ treatment

• Main Authors: Chiu-YingHuang, 黃秋瑛
• Other Authors: Jih-Ing Chuang
• Format: Others
• Language: en_US
• Published: 2012
• Online Access: http://ndltd.ncl.edu.tw/handle/93010998358963392315

碩士 === 國立成功大學 === 生理學研究所 === 100 === Mitochondrial dysfunction is an early event of cell death in neurodegenerative diseases, such as Parkinson’s disease. Mitochondrial dynamic of fusion and fission is respectively controlled by the expression of mitofusion (Mfn) and dynamin-related GTPase (Drp1). Our preliminary results showed that a Drp1-dependent mitochondrial fission was related to neuron death in a 1-methyl-4-phenylpyridinium (MPP+)-induced parkinsonian model. We also found that cells cultured in 32°C (mild cold exposure) reduced MPP+-induced cell death and prolonged cell cycle, which were associated with a decreased expression of cyclin-dependent kinases (CDKs). Recent studies demonstrated that mitochondrial dynamic change at different stages of cell cycle, and CDK5 involved in the regulation of mitochondrial fission during neuron apoptosis. Herein, we investigated whether cold exposure protects neurons from MPP+ intoxication by reducing the Drp1-dependent mitochondrial fission and modulating the expression of CDK4/5. We found that cold exposure significantly reduced MPP+-induced mitochondrial fission in mitoDsRed-labeled human SK-N-SH cells and rat primary cortical neurons. Cold exposure induced downregulation of CDK4 and cyclinD1, as well as upregulation of p27 (CDK4 inhibitor) and p35 (CDK5 partner) protein expression, indicating that p27 and p35 involved in cold exposure-induced cell cycle arrest and neuroprotection. We also found that the inhibition of CDK4/5 by CDK4 inhibitor and roscovitine imitated the effect of cold exposure to inhibit MPP+-induced mitochondrial fission and neuron death. Cold exposure and inhibition of CDK4/5 attenuated MPP+-induced upregulation of mitochondrial Drp1 and Mfn2 protein expression in primary cortical neurons. The results reveal that cold exposure may regulate CDK4 and CDK5 activity to inhibit Drp1-associated mitochondrial fission and neuron death in MPP+-induced Parkinsonian model.