α-synuclein promotes neuroprotection through NF-κB-mediated transcriptional regulation of protein kinase Cδ.
Parkinson's disease (PD) is a neurodegenerative disorder that results in a progressively debilitating loss of motor function and hypokinesia and is characterized by the selective loss of dopaminergic neurons in the substantia nigra pars compacta. Recent evidence suggests that caspase-3-dependent proteolytic cleavage and nuclear translocation of the δ isoform of protein kinase C (PKCδ) may be required for oxidative stress-induced dopaminergic cell death. Whereas several proteins have been postulated to contribute to dopaminergic neuron loss, the signaling cascades that mediate this selective neuron loss in PD are not well understood. The presynaptic protein α-synuclein (α-syn), mutations in which cause familial PD, has been implicated in pathways that influence both neuronal protection and apoptosis. However, the activities of α-syn in PD have not been elucidated at the molecular level, and whether α-syn is neuroprotective or neurotoxic remains controversial. This Journal Club discusses recent research indicating that α-syn may protect against dopaminergic cell death by down-regulating PKCδ, a key molecule that mediates apoptosis in these cells. These findings are the first steps toward the understanding of critical signaling pathways that might be important in PD pathogenesis and represent potential targets for developing new therapies.
Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Reina
R
Aoki
Yun Rose
YR
Li
D017209:Apoptosis; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051745:Protein Kinase C-delta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
D016328:NF-kappa B; D051844:alpha-Synuclein; D051745:Protein Kinase C-delta