Modulating the Catalytic Activity of AMPK Has Neuroprotective Effects Against α-synuclein Toxicity

Overview

Journal Mol Neurodegener

Publisher Biomed Central

Specialties Molecular Biology
Neurology

Date 2017 Nov 5

PMID 29100525

Citations 24

Authors

Wojciech Bobela

Sameer Nazeeruddin

Graham Knott

Patrick Aebischer

Bernard L Schneider

Affiliations

Soon will be listed here.

Abstract

Background: Metabolic perturbations and slower renewal of cellular components associated with aging increase the risk of Parkinson's disease (PD). Declining activity of AMPK, a critical cellular energy sensor, may therefore contribute to neurodegeneration.

Methods: Here, we overexpress various genetic variants of the catalytic AMPKα subunit to determine how AMPK activity affects the survival and function of neurons overexpressing human α-synuclein in vivo.

Results: Both AMPKα1 and α2 subunits have neuroprotective effects against human α-synuclein toxicity in nigral dopaminergic neurons. Remarkably, a modified variant of AMPKα1 (T172Dα1) with constitutive low activity most effectively prevents the loss of dopamine neurons, as well as the motor impairments caused by α-synuclein accumulation. In the striatum, T172Dα1 decreases the formation of dystrophic axons, which contain aggregated α-synuclein. In primary cortical neurons, overexpression of human α-synuclein perturbs mitochondrial and lysosomal activities. Co-expressing AMPKα with α-synuclein induces compensatory changes, which limit the accumulation of lysosomal material and increase the mitochondrial mass.

Conclusions: Together, these results indicate that modulating AMPK activity can mitigate α-synuclein toxicity in nigral dopamine neurons, which may have implications for the development of neuroprotective treatments against PD.

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References

Castillo K, Valenzuela V, Matus S, Nassif M, Onate M, Fuentealba Y . Measurement of autophagy flux in the nervous system in vivo. Cell Death Dis. 2013; 4:e917. PMC: 3847309. DOI: 10.1038/cddis.2013.421. View

Stein S, Woods A, Jones N, Davison M, Carling D . The regulation of AMP-activated protein kinase by phosphorylation. Biochem J. 2000; 345 Pt 3:437-43. PMC: 1220775. View

Decressac M, Mattsson B, Weikop P, Lundblad M, Jakobsson J, Bjorklund A . TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity. Proc Natl Acad Sci U S A. 2013; 110(19):E1817-26. PMC: 3651458. DOI: 10.1073/pnas.1305623110. View

Ciron C, Lengacher S, Dusonchet J, Aebischer P, Schneider B . Sustained expression of PGC-1α in the rat nigrostriatal system selectively impairs dopaminergic function. Hum Mol Genet. 2012; 21(8):1861-76. PMC: 3313800. DOI: 10.1093/hmg/ddr618. View

Dettmer U, Selkoe D, Bartels T . New insights into cellular α-synuclein homeostasis in health and disease. Curr Opin Neurobiol. 2015; 36:15-22. DOI: 10.1016/j.conb.2015.07.007. View

Johanns M, Pyr Dit Ruys S, Houddane A, Vertommen D, Herinckx G, Hue L . Direct and indirect activation of eukaryotic elongation factor 2 kinase by AMP-activated protein kinase. Cell Signal. 2017; 36:212-221. DOI: 10.1016/j.cellsig.2017.05.010. View

Jornayvaz F, Samuel V, Shulman G . The role of muscle insulin resistance in the pathogenesis of atherogenic dyslipidemia and nonalcoholic fatty liver disease associated with the metabolic syndrome. Annu Rev Nutr. 2010; 30:273-90. PMC: 3730129. DOI: 10.1146/annurev.nutr.012809.104726. View

Dulovic M, Jovanovic M, Xilouri M, Stefanis L, Harhaji-Trajkovic L, Kravic-Stevovic T . The protective role of AMP-activated protein kinase in alpha-synuclein neurotoxicity in vitro. Neurobiol Dis. 2013; 63:1-11. DOI: 10.1016/j.nbd.2013.11.002. View

Grahame Hardie D . AMPK: positive and negative regulation, and its role in whole-body energy homeostasis. Curr Opin Cell Biol. 2014; 33:1-7. DOI: 10.1016/j.ceb.2014.09.004. View

10.

Vingtdeux V, Giliberto L, Zhao H, Chandakkar P, Wu Q, Simon J . AMP-activated protein kinase signaling activation by resveratrol modulates amyloid-beta peptide metabolism. J Biol Chem. 2010; 285(12):9100-13. PMC: 2838330. DOI: 10.1074/jbc.M109.060061. View

11.

Su X, Chu Y, Kordower J, Li B, Cao H, Huang L . PGC-1α Promoter Methylation in Parkinson's Disease. PLoS One. 2015; 10(8):e0134087. PMC: 4552803. DOI: 10.1371/journal.pone.0134087. View

12.

Gowans G, Hawley S, Ross F, Grahame Hardie D . AMP is a true physiological regulator of AMP-activated protein kinase by both allosteric activation and enhancing net phosphorylation. Cell Metab. 2013; 18(4):556-66. PMC: 3791399. DOI: 10.1016/j.cmet.2013.08.019. View

13.

Ulgherait M, Rana A, Rera M, Graniel J, Walker D . AMPK modulates tissue and organismal aging in a non-cell-autonomous manner. Cell Rep. 2014; 8(6):1767-1780. PMC: 4177313. DOI: 10.1016/j.celrep.2014.08.006. View

14.

Suter M, Riek U, Tuerk R, Schlattner U, Wallimann T, Neumann D . Dissecting the role of 5'-AMP for allosteric stimulation, activation, and deactivation of AMP-activated protein kinase. J Biol Chem. 2006; 281(43):32207-16. DOI: 10.1074/jbc.M606357200. View

15.

Lashuel H, Overk C, Oueslati A, Masliah E . The many faces of α-synuclein: from structure and toxicity to therapeutic target. Nat Rev Neurosci. 2012; 14(1):38-48. PMC: 4295774. DOI: 10.1038/nrn3406. View

16.

Liang C, Wang T, Luby-Phelps K, German D . Mitochondria mass is low in mouse substantia nigra dopamine neurons: implications for Parkinson's disease. Exp Neurol. 2006; 203(2):370-80. DOI: 10.1016/j.expneurol.2006.08.015. View

17.

Gaugler M, Genc O, Bobela W, Mohanna S, Ardah M, El-Agnaf O . Nigrostriatal overabundance of α-synuclein leads to decreased vesicle density and deficits in dopamine release that correlate with reduced motor activity. Acta Neuropathol. 2012; 123(5):653-69. DOI: 10.1007/s00401-012-0963-y. View

18.

Wahlqvist M, Lee M, Hsu C, Chuang S, Lee J, Tsai H . Metformin-inclusive sulfonylurea therapy reduces the risk of Parkinson's disease occurring with Type 2 diabetes in a Taiwanese population cohort. Parkinsonism Relat Disord. 2012; 18(6):753-8. DOI: 10.1016/j.parkreldis.2012.03.010. View

19.

Baskin K, Taegtmeyer H . AMP-activated protein kinase regulates E3 ligases in rodent heart. Circ Res. 2011; 109(10):1153-61. PMC: 3254015. DOI: 10.1161/CIRCRESAHA.111.252742. View

20.

Vergouts M, Marinangeli C, Ingelbrecht C, Genard G, Schakman O, Sternotte A . Early ALS-type gait abnormalities in AMP-dependent protein kinase-deficient mice suggest a role for this metabolic sensor in early stages of the disease. Metab Brain Dis. 2015; 30(6):1369-77. DOI: 10.1007/s11011-015-9706-9. View