Involvement of glyceraldehyde-3-phosphate dehydrogenase in rotenone-induced cell apoptosis: relevance to protein misfolding and aggregation.
The hallmarks of Parkinson's disease (PD) are the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the presence of intracellular inclusion bodies in surviving neurons. Although the specific etiology and pathogenesis of sporadic PD remains unknown, neuronal death was proven to be associated with mitochondrial dysfunction and protein misfolding. However, molecular links between mitochondrial dysfunction and protein misfolding remains obscure. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a classical glycolytic enzyme, is responsible for carbohydrate metabolism under normal circumstances. When translocated to the nucleus, GAPDH promotes neuron apoptosis in several neurodegenerative disorders. But it seems that GAPDH translocation is not the sole mechanism responsible for neuronal apoptosis. We found that rotenone, a common mitochondrial complex I inhibitor used to produce experimental parkinsonism, cannot only induce GAPDH translocation but also trigger intermolecular disulfide bonding and result in the formation of intracytoplasmic aggregates of GAPDH. This suggests a link between mitochondrial dysfunction and protein misfolding, and sheds light on the pathophysiology of Lewy body formation in Parkinson's disease.
Huang
Jinsha
J
Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Hao
Lijun
L
Xiong
Nian
N
Cao
Xuebin
X
Liang
Zhihou
Z
Sun
Shenggang
S
Wang
Tao
T
D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D016716:PC12 Cells; D017510:Protein Folding / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D012402:Rotenone / Q000633:toxicity*; D012995:Solubility / Q000187:drug effects; D013997:Time Factors; D014475:Uncoupling Agents / Q000633:toxicity*
D012333:RNA, Messenger; D014475:Uncoupling Agents; D012402:Rotenone; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases