Neuroprotective mechanisms of the Rheb/mTORC1 signaling pathway in the adult dopaminergic system in vivo

Despite intensive research effort, no effective pharmacological therapies for Parkinson’s disease (PD) have been developed. However, with the development of efficient gene delivery systems, gene therapy for PD has become a focus of research, and increasing evidences suggest that continuous production of neurotrophic factors plays a significant role in the functional restoration of the nigrostriatal dopaminergic (DA) system. We recently reported that viral vector-mediated hRheb(S16H) expression robustly induced glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) expression in adult DA neurons in vivo. Furthermore, we showed that hRheb (S16H)-induced neurotrophic factor expression was dependent on mTORC1 activity and protected nigrostriatal DA projections. Our observations suggest that hRheb (S16H) expression in mature DA neurons facilitates the production of diverse neurotrophic factors such as GDNF and BDNF, and that multiple factors are involved in the maintenance and protection of the nigrostriatal DA system in the adult brain. In this research highlight, we provide a brief overview of our most recent published findings, which demonstrate the neuroprotective mechanisms of hRheb (S16H) on nigrostriatal DA projections in vivo.