Necdin, a growth suppressor expressed predominantly in postmitotic neurons, interacts with transcription factors E2F1 and p53. Mitochondrial dysfunction plays central roles in the pathophysiology of neurodegenerative disease including Parkinson's disease. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-la) is master regulator in mitochondrial biogenesis. Necdin promotes neuronal mitochondrial biogene- sis induced by enhanced PGC-la expression in neuron. Necdin binds and strongly stabilizes PGC-la by inhibiting its ubiquitin-proteasomal degradation. Necdin KO mice aggravates MPTP-induced dopaminergic neuronal loss. In the adult mice, AAV-mediated overexpression of necdin in the substantia nigra leads to significant neuroprotection in experimental Parkinson's disease. These findings demonstrate that necdin promotes mitochondrial biogenesis mediated by stabilization of endogenous PGC-la protein to enhance neuroprotection against neurodegenerative disease by mitochondriallInsults.