DNA polymerase-beta is required for 1-methyl-4-phenylpyridinium-induced apoptotic death in neurons.
The biochemical pathways that mediate the degeneration of dopaminergic neurons in the substantia nigra of patients with Parkinson's disease are largely unknown. Recently, aberrant cell cycle events have been shown to be associated with neuronal death in several neurodegenerative diseases. In the present study, we investigated the role of DNA polymerases (DNA pols) in 1-methyl-4-phenylpyridinium (MPP(+))-induced neuronal apoptosis in cerebellar granule cells. After exposure to MPP(+), the neurons entered S phase of the cell cycle. Neuronal cell cycle re-entry and apoptosis were attenuated by flavopiridol, which is a broad inhibitor of cyclin-dependent kinases (CDKs). MPP(+) exposure significantly increased the expression of DNA pol-beta and primase but did not affect the expression of the canonical replicative DNA pols, including DNA pol-delta and pol-epsilon. Dideoxycytidine, which is a pharmacological inhibitor of DNA pol-beta, attenuated the neuronal apoptosis mediated by MPP(+). In a similar manner, the expression of a dominant negative form of DNA pol-beta was also neuroprotective. These results suggest that DNA pol-beta may have a causal role in MPP(+)-induced neuronal apoptosis.
Zhang
Zhentao
Z
Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, People's Republic of China.
Cao
Xuebing
X
Xiong
Nian
N
Wang
Hongcai
H
Huang
Jinsha
J
Sun
Shenggang
S
Liang
Zhihou
Z
Wang
Tao
T
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism; D019951:DNA Polymerase beta / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D018844:Cyclin-Dependent Kinases; D019951:DNA Polymerase beta; D015655:1-Methyl-4-phenylpyridinium