Activation of CNTF/CNTFR alpha Signaling Pathway by hRheb(S16H) Transduction of Dopaminergic Neurons In Vivo

作者：Jeong Kyoung Hoon; Nam Jin Han; Jin Byung Kwan; Kim Sang Ryong^*

来源：PLos One, 2015, 10(3): e0121803.

DOI：10.1371/journal.pone.0121803

Ciliary neurotrophic factor (CNTF) is one of representative neurotrophic factors for the survival of dopaminergic neurons. Its effects are primarily mediated via CNTF receptor a (CNTFR alpha). It is still unclear whether the levels of CNTFR alpha change in the substantia nigra of Parkinson's disease (PD) patients, but CNTF expression shows the remarkable decrease in dopaminergic neurons in the substantia nigra pars compacta (SNpc), suggesting that the support of CNTF/CNTFR alpha signaling pathway may be a useful neuroprotective strategy for the nigrostriatal dopaminergic projection in the adult brain. Here, we report that transduction of rat SNpc dopaminergic neurons by adeno-associated virus with a gene encoding human ras homolog enriched in brain (hRheb), with an S16H mutation [hRheb(S16H)], significantly upregulated the levels of both CNTF and CNTFR alpha in dopaminergic neurons. Moreover, the hRheb(S16H)-activated CNTF/CNTFR alpha signaling pathway was protective against 1-methyl-4-phenylpyridinium-induced neurotoxicity in the nigrostriatal dopaminergic projections. These results suggest that activation of CNTF/CNTFR alpha signaling pathway by specific gene delivery such as hRheb(S16H) may have therapeutic potential in the treatment of PD.

• 出版日期2015-3-23