Activation of Cdk4/cyclin D1 Pathway Participates in the Neuronal Degeneration of Murine Niemann-Pick Disease Type C

Abstract: To investigate pathogenesis of pathological axonal spheroids in Niemann-Pick disease type C (NPC)， a murine model of NPC， the Balb/c nih npc-1 mouse strain， has been studied using immunohistochemical and immunoblot techniques， to explore activation of cdk4/cyclin D1/Rb2 pathway and its association with neurodegeneration and hyperphosphorylated neurofilament. Expressions of cdk4 and cyclin D1 were prominent in the abnormally expanded axonal spheroids， distributed in the white matter of the brainstem， basal ganglia， cerebellum and cerebrum of npc-/- mice aged 4 to 12 weeks. The initial accumulation of cdk4 and cyclin D1 was found to be in the brainstem at the age of 4 weeks， and than to slowly involve the other regions of the white matter with advance of age. Rb2/p130， a member of retinoblastoma protein (Rb) family， was observed to be abnormally hyperphosphorylated and enriched in the axonal spheroids as well. The distribution of phosphorylated neurofilament， detected by SMI31 monoclonal antibody， was in a perfect colocalization with cdk4 immunoreactivity in time and space. The up-regulation of cdk4/cyclin D1/Rb2 was further substantiated by immunoblotting analyses， to be increased by up to 2-folds (P<0.05， t test). In conclusion， abnormal activation of cdk4/cyclin D1 is closely associated with formation of the axonal spheroids in the murine model of Niemann-Pick disease type C， and with abnormal phosphorylation of neurofilament as well. The pathway could be a target for intervention to save the degenerating neurons in NPC.

CSTR: 32200.14.cjcb.2005.04.0017