The protective role of AMP-activated protein kinase in alpha-synuclein neurotoxicity in vitro

Marija Dulovic, Maja Jovanovic, Maria Xilouri, Leonidas Stefanis, Ljubica Harhaji-Trajkovic, Tamara Kravic-Stevovic, Verica Paunovic, Mustafa T. Ardah, Omar M.A. El-Agnaf, Vladimir Kostic, Ivanka Markovic, Vladimir Trajkovic

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66 Citations (Scopus)

Abstract

In the present study, we investigated the role of the main intracellular energy sensor, AMP-activated protein kinase (AMPK), in the in vitro neurotoxicity of α-synuclein (ASYN), one of the key culprits in the pathogenesis of Parkinson's disease. The loss of viability in retinoic acid-differentiated SH-SY5Y human neuroblastoma cells inducibly overexpressing wild-type ASYN was associated with the reduced activation of AMPK and its activator LKB1, as well as AMPK target Raptor. ASYN-overexpressing rat primary neurons also displayed lower activity of LKB1/AMPK/Raptor pathway. Restoration of AMPK activity by metformin or AICAR reduced the in vitro neurotoxicity of ASYN overexpression, acting independently of the prosurvival kinase Akt or the induction of autophagic response. The conditioned medium from ASYN-overexpressing cells, containing secreted ASYN, as well as dopamine-modified or nitrated recombinant ASYN oligomers, all inhibited AMPK activation in differentiated SH-SY5Y cells and reduced their viability, but not in the presence of metformin or AICAR. The RNA interference-mediated knockdown of AMPK increased the sensitivity of SH-SY5Y cells to the harmful effects of secreted ASYN. AMPK-dependent protection from extracellular ASYN was also observed in rat neuron-like pheochromocytoma cell line PC12. These data demonstrate the protective role of AMPK against the toxicity of both intracellular and extracellular ASYN, suggesting that modulation of AMPK activity may be a promising therapeutic strategy in Parkinson's disease.

Original languageEnglish
Pages (from-to)1-11
Number of pages11
JournalNeurobiology of Disease
Volume63
DOIs
Publication statusPublished - Mar 2014

Keywords

  • AICAR
  • AMPK
  • Akt
  • Alpha-synuclein
  • Autophagy
  • Metformin
  • Neuroprotection
  • Neurotoxicity

ASJC Scopus subject areas

  • Neurology

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  • Cite this

    Dulovic, M., Jovanovic, M., Xilouri, M., Stefanis, L., Harhaji-Trajkovic, L., Kravic-Stevovic, T., Paunovic, V., Ardah, M. T., El-Agnaf, O. M. A., Kostic, V., Markovic, I., & Trajkovic, V. (2014). The protective role of AMP-activated protein kinase in alpha-synuclein neurotoxicity in vitro. Neurobiology of Disease, 63, 1-11. https://doi.org/10.1016/j.nbd.2013.11.002