p70S6K on astrocytes protects dopamine neurons from 1‐methyl‐4‐phenylpyridinium neurotoxicity

Our recent finding has demonstrated that astrocytes confer neuroprotection by endogenously producing ciliary neurotrophic factor (CNTF) via transient receptor potential vanilloid 1 (TRPV1) in Parkinson's disease (PD). In this study, the possible molecular target for TRPV1‐mediated CNTF production and its neuroprotective effects on dopamine neurons were further investigated. For comparison, glial cell‐line derived neurotrophic factor (GDNF) was also examined. The results show that TRPV1‐ribosomal protein 70 S6 kinase (p70S6K) signaling on astrocytes produces endogenous CNTF in the SN of MPP+‐lesioned rat. By marked contrast, the expression of GDNF on astrocytes is independent of TRPV1‐p70S6K signaling. Administration of a TRPV1 agonist, capsaicin, increases levels of phosphorylated p70S6K (p‐p70S6K; activation of p70S6K) on astrocytes, resulting in the survival of dopamine neurons and behavioral recovery through endogenous production of CNTF in the MPP+‐lesioned rat model of PD. Immunohistochemical analysis reveals expression of p‐p70S6K on astrocytes in the SN of PD patients, indicating relevance to human PD. The present in vivo data is the first to demonstrate that astrocytic TRPV1‐p70S6K signaling plays a pivotal role as endogenous neuroprotective, and it may constitute a novel therapeutic target for treating PD. Main Points Activation of TRPV1‐p70S6K‐CNTF signaling on astrocytes protects dopamine neurons from MPP+‐ neurotoxicity and improves motor behavior. Phosphorylated p70S6K is expressed in astrocytes in human PD SN.