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

Cell Signal. 2014 Aug;26(8):1680-1689. doi: 10.1016/j.cellsig.2014.04.009. Epub 2014 Apr 12.

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.

Keywords: AMPK; Akt; Neuronal cells; Parkinson's disease; mTOR.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-4-phenylpyridinium / toxicity
  • AMP-Activated Protein Kinases / metabolism*
  • Animals
  • Apoptosis / drug effects
  • Carrier Proteins / antagonists & inhibitors
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Caspase 3 / metabolism
  • Cell Survival / drug effects
  • Cells, Cultured
  • Intracellular Signaling Peptides and Proteins
  • Models, Biological
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Oxidopamine / toxicity
  • PC12 Cells
  • Parkinson Disease / metabolism
  • Parkinson Disease / pathology
  • Phosphoproteins / antagonists & inhibitors
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Rats
  • Ribosomal Protein S6 Kinases / metabolism*
  • Rotenone / toxicity
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Carrier Proteins
  • Eif4ebp1 protein, rat
  • Intracellular Signaling Peptides and Proteins
  • Phosphoproteins
  • Rotenone
  • Oxidopamine
  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases
  • Rps6kb1 protein, rat
  • AMP-Activated Protein Kinases
  • Caspase 3
  • 1-Methyl-4-phenylpyridinium