Activation of AMPK and inactivation of Akt result in suppression of mTOR-mediated S6K1 and 4E-BP1 pathways leading to neuronal cell death in in vitro models of Parkinson's disease

Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons. Dysregulation of mammalian target of rapamycin (mTOR) has been implicated in the pathogenesis of PD. However, the underlying mechanism is incompletely elucidated. Here, we show that PD mimetics (6-hydroxydopamine, N-methyl-4-phenylpyridine or rotenone) suppressed phosphorylation of mTOR, S6K1 and 4E-BP1, reduced cell viability, and activated caspase-3 and PARP in PC12 cells and primary neurons. Overexpression of wild-type mTOR or constitutively active S6K1, or downregulation of 4E-BP1 in PC12 cells partially prevented cell death in response to the PD toxins, revealing that mTOR-mediated S6K1 and 4E-BP1 pathways due to the PD toxins were inhibited, leading to neuronal cell death. Furthermore, we found that the inhibition of mTOR signaling contributing to neuronal cell death was attributed to suppression of Akt and activation of AMPK. This is supported by the findings that ectopic expression of constitutively active Akt or dominant negative AMPKα, or inhibition of AMPKα with compound C partially attenuated inhibition of phosphorylation of mTOR, S6K1 and 4E-BP1, activation of caspase-3, and neuronal cell death triggered by the PD toxins. The results indicate that PD stresses activate AMPK and inactivate Akt, causing neuronal cell death via inhibiting mTOR-mediated S6K1 and 4E-BP1 pathways. Our findings suggest that proper co-manipulation of AMPK/Akt/mTOR signaling may be a potential strategy for prevention and treatment of PD.

4-Nonylphenol induces autophagy and attenuates mTOR-p70S6K/4EBP1 signaling by modulating AMPK activation in Sertoli cells

“…Interestingly, we also identified that AMPK signaling is responsible for NP-induced mTOR inhibition in SCs. AMPK has been shown to dephosphorylate TSC2, which inhibits mTOR activity and stimulates autophagy (Tanwar et al 2012;Wu et al 2015;Xu et al 2014). As in our study, specifically inducing activation of AMPK with AICAR further decreased the phosphorylation of TSC2 in NP-treated SCs, whereas pharmacological blockade and siRNA-mediated knockdown of AMPK inhibited it.…”

“…The present study revealed that treatment of NP robustly phosphorylated and activated AMPK, and simultaneously suppressed TSC2 and mTOR activity in testis. mTOR has been recognized as a central controller for cell growth and survival because of its important role in regulating multiple cellular processes, in particular protein synthesis as well as autophagy (Xu et al 2014). Noteworthy, previously we showed up-regulation of AMPK as well as down-regulation of TSC2 and mTOR phosphorylation in NP-treated SCs (Duan et al 2016c).…”

Role of metabolism in neurodegenerative disorders

“…In contrast, overexpression of wild-type mTOR or constitutively active S6K1 prevented cell death in response to the PD toxins, whereas inhibition of mTOR signaling contributed to neuronal cell death, following suppression of Akt and activation of AMPK[106]. On the other hand, mTOR activation can prevent oxidative stress-mediated autophagy in dopamine neurons[107] and prolonged activation of this pathway can lead to dyskinesia in patients with PD [108](Figure 1).This is testified by the finding showing that mTOR inhibitor Temsirolimus (CCI-779)alleviates the severity of dyskinesia in L-3,4-dihydroxyphenylalanine (L-DOPA)-primed animals, as a result of the reduced activation of mTOR signaling in striatal medium spiny neurons[109].…”

Targeting AMPK Signaling as a Neuroprotective Strategy in Parkinson’s Disease

“…In both primary neurons and PC12 cells, administration of 6-OHDA, rotenone, or MPP+ each increased AMPK activity, decreased cell viability, and promoted apoptosis. Cell viability was improved by inhibiting AMPK with compound C, expressing AMPK-DN, or by inhibiting macroautophagy through overexpression of mTORC1 [200]. …”