We previously demonstrated that CRMP5 (CRAM)-associated GTPase (CRAG), a short splicing variant of centaurin-γ3/AGAP3, facilitated degradation of misfolded proteins including expanded polyglutamine protein (polyQ) via the nuclear ubiquitin-proteasome pathway. Taking advantage of this feature, we previously showed that lentivirus-mediated CRAG expression in the Purkinje cells of mice expressing polyQ resulted in clearance of the polyQ aggregates and rescue from ataxia. Furthermore, we found that CRAG, but not centaurin-γ3, induces transcriptional activation of c-fos-dependent activator protein-1 (AP-1) via serum response factor (SRF). Thus, CRAG enhances the cell survival signal against the accumulation of misfolded proteins through not only proteasome activation, but also the activation of SRF-c-fos-mediated AP-1 activation in vitro. However, the function of CRAG in vivo remains unknown. Here we generated and analyzed CRAG-deficient mice. CRAG-deficient mice showed abnormal behavior and lethality within one mouth after birth due to neuronal dysfunction. Histological analysis indicated neuronal cell death and atrophy in CRAG-deficient mice. In this meeting, we discuss the mechanism underlying neuronal dysfunction caused by CRAG knockout. Our findings further extend the usefulness of targeted delivery of CRAG as a gene therapy for neurodegenerative diseases.