The Mitochondrial Toxin 3-Nitropropionic Acid Induces Striatal Neurodegeneration via a c-Jun N-Terminal Kinase/c-Jun Module

摘要: Impairments in mitochondrial energy metabolism are thought to be involved most neurodegenerative diseases, including Huntington's disease (HD). Chronic administration of 3-nitropropionic acid (3-NP), a suicide inhibitor succinate dehydrogenase, causes prolonged impairments and replicates the pathophysiological features HD, preferential striatal degeneration. In this study, we analyzed one mechanisms that could account for selective 3-NP-induced chronically 3-NP-infused rats, time course motor behavioral histological abnormalities was determined. Progressive alterations performance occurred after 3 d. By analysis terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end-labeling staining, found neurodegenerescence striatum, occurring first its dorsolateral (DL) part. Activation c-Jun N-terminal kinase (JNK) from brain sections these using immunocytochemical detection phosphorylated form. JNK progressively selectively DL striatum followed by activation expression same region. To elucidate role JNK/c-Jun module degeneration, then used primary neurons culture, which replicated neuronal death application 3-NP. We strong nuclear translocation activated rapidly phosphorylation transcription factor c-Jun. Overexpression dominant negative version c-Jun, lacking transactivation domain sites JNK, completely abolished neurodegeneration. thus conclude genetic program controlled is an important molecular event