Elucidation of molecular signaling mechanism of axonal guidance

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Semaphorins play a critical role in axon guidance as repulsive factors and CRMP family proteins are believed to be involved in semaphorin signaling. We have identified a novel GTPase named CRAG containing a nuclear localization signal sequence (NLS) as a binding protein of collapsin response mediator protein (CRMP) -associated molecule (CRAM ICRMP-51) . In neurons, CRAG plays an important role for reactive oxygen species (ROS) -mediated stress response including semaphorin3A signaling. Interestingly, CRAG forms unique nuclear inclusion associated with PML bodies after stimulation of semaphorin3A. This result supports that semaphorins utilize redox signaling and provides new concept that semaphorins may regulate transcriptional regulation in nudes by activation of CRAG.On the other hand, CRAG was found to be involved in the molecular mechanism of polyglutamine disease. Actually, CRAG associates with and PML, leading to a large ling-like stnicture of PML body with ubiquitination which is characteristic of polyglutamine diseases. Importantly, CRAG promoted a rapid degradation of misfolded polyglutamine proteins in the nuclear inclusions through ubiquitin-proteasome pathway and attenuated their cell toxicity. Most recently, we showed that lentivector-mediated CRAG expression in cerebellar neurons cleared PolyQ aggregates and strikingly ameliorated severe ataxia in model mice of polyglutamine disease.In the near future, targeted expression of CRAG is a potential gene therapy for human polyglutamine diseases.