Induction of GDNF and BDNF by hRheb(S16H) Transduction of SNpc Neurons: Neuroprotective Mechanisms of hRheb(S16H) in a Model of Parkinson’s Disease

Abstract

The transduction of dopaminergic (DA) neurons with human ras homolog enriched in brain, which has a S16H mutation [hRheb(S16H)] protects the nigrostriatal DA projection in the 6-hydroxydopamine (6-OHDA)-treated animal model of Parkinson's disease (PD). However, it is still unclear whether the expression of active hRheb induces the production of neurotrophic factors such as glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), which are involved in neuroprotection, in mature neurons. Here, we show that transduction of nigral DA neurons with hRheb(S16H) significantly increases the levels of phospho-cyclic adenosine monophosphate (cAMP) response element-binding protein (p-CREB), GDNF, and BDNF in neurons, which are attenuated by rapamycin, a specific inhibitor of mammalian target of rapamycin complex 1 (mTORC1). Moreover, treatment with specific neutralizing antibodies for GDNF and BDNF reduced the protective effects of hRheb(S16H) against 1-methyl-4-phenylpyridinium (MPP(+))-induced neurotoxicity. These results show that activation of hRheb/mTORC1 signaling pathway could impart to DA neurons the important ability to continuously produce GDNF and BDNF as therapeutic agents against PD.

TRPV1 on astrocytes rescues nigral dopamine neurons in Parkinson’s disease via CNTF

“…Optical densities of the TH + striatal fibres were measured using Science Lab 2001 Image Gauge (Fujifilm) (Nam et al, 2015).…”

Roles of Rheb(S16H) in substantia nigra pars compacta dopaminergic neurons in vivo

“…Thus, replacement strategies to supplement neurotrophic factors are considered potential therapeutic approaches for PD. Our recent study found that the activation of mTORC1 by Rheb(S16H) transduction of DA neurons induced the production of trophic factors, such as GDNF and BDNF, and that the endogenous production of those factors contributed to the neuroprotection by Rheb(S16H) transduction in a neurotoxin model of PD (20). The present study describes the importance of Rheb(S16H) transduction of DA neurons in the adult brain, indicating a potential therapeutic method for PD.…”

“…Furthermore, the serine at position 16 of Rheb has sensitivity to TSC activation and Rheb(S16H), a mutation of the serine to histidine, exhibits resistance to GTPase activation by TSC (8,29), indicating that Rheb(S16H) is a strong activator of mTORC1. Our recent studies demonstrated that Rheb(S16H) expression in DA neurons induced an increase in phosphorylation of the mTORC1 substrates, 4E-BP1 and p70S6K, indicating activation of mTORC1 and showed apparent neurotrophic effects in the nigrostriatal DA system in the adult brains (8,20). Additionally, the activation of mTORC1 by Rheb(S16H) transduction of DA neurons resulted in neuroprotective effects on the nigrostriatal DA projection in rat and mouse models of PD, indicating that Rheb(S16H) transduction of SN pars compacta neurons may have a common effect against different neurotoxins and models associated with the degeneration of the nigrostriatal DA projection in the adult brain.…”

Rheb in neuronal degeneration, regeneration, and connectivity

“…Several studies were conducted in analyzing the neuroprotective roles of Rheb by axon regeneration or increased survival in different neuron types Nam et al, 2015;Wu et al, 2016) (Figure 1). Interestingly, the fact that the adult mammalian central nervous system (CNS) is incapable of an axonal regenerative response after injury has been challenged by the recent work by Park et al showing that constitutive activation of Akt-mTORC1 signaling in adult retinal ganglion neurons prior to optic nerve injury promoted regeneration of their axons (Park et al, 2008;Kim et al, 2012).…”

“…Brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) are required for regulating the development, maintenance function and plasticity of mature neurons and hence are important in protection of neurons in Parkinson's diseases (PD), which is characterized by progressive degeneration of dopaminergic (DA) neurons (Kim et al, 2012;Jeon and Kim, 2015;Nam et al, 2015). Transduction of DA neurons with adenoassociated virus constructs containing a constitutively active form of Rheb (AAV-hRheb S16H), provided protection of DA neurons from 1-methyl-4-phenylpyridine (MPP) induced degeneration in adult brain.…”