Modulating the catalytic activity of AMPK has neuroprotective effects against α-synuclein toxicity
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 variou...
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doaj-701c2634887a482ba26dc2d0ce8ba3432020-11-25T00:38:14ZengBMCMolecular Neurodegeneration1750-13262017-11-0112111910.1186/s13024-017-0220-xModulating the catalytic activity of AMPK has neuroprotective effects against α-synuclein toxicityWojciech Bobela0Sameer Nazeeruddin1Graham Knott2Patrick Aebischer3Bernard L. Schneider4Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL)Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL)Centre of Interdisciplinary Electron Microscopy, Ecole Polytechnique Fédérale de Lausanne (EPFL)Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL)Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL)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.http://link.springer.com/article/10.1186/s13024-017-0220-xAgingAMPKα-synucleinNeuroprotectionParkinson’s disease |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Wojciech Bobela Sameer Nazeeruddin Graham Knott Patrick Aebischer Bernard L. Schneider |
spellingShingle |
Wojciech Bobela Sameer Nazeeruddin Graham Knott Patrick Aebischer Bernard L. Schneider Modulating the catalytic activity of AMPK has neuroprotective effects against α-synuclein toxicity Molecular Neurodegeneration Aging AMPK α-synuclein Neuroprotection Parkinson’s disease |
author_facet |
Wojciech Bobela Sameer Nazeeruddin Graham Knott Patrick Aebischer Bernard L. Schneider |
author_sort |
Wojciech Bobela |
title |
Modulating the catalytic activity of AMPK has neuroprotective effects against α-synuclein toxicity |
title_short |
Modulating the catalytic activity of AMPK has neuroprotective effects against α-synuclein toxicity |
title_full |
Modulating the catalytic activity of AMPK has neuroprotective effects against α-synuclein toxicity |
title_fullStr |
Modulating the catalytic activity of AMPK has neuroprotective effects against α-synuclein toxicity |
title_full_unstemmed |
Modulating the catalytic activity of AMPK has neuroprotective effects against α-synuclein toxicity |
title_sort |
modulating the catalytic activity of ampk has neuroprotective effects against α-synuclein toxicity |
publisher |
BMC |
series |
Molecular Neurodegeneration |
issn |
1750-1326 |
publishDate |
2017-11-01 |
description |
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. |
topic |
Aging AMPK α-synuclein Neuroprotection Parkinson’s disease |
url |
http://link.springer.com/article/10.1186/s13024-017-0220-x |
work_keys_str_mv |
AT wojciechbobela modulatingthecatalyticactivityofampkhasneuroprotectiveeffectsagainstasynucleintoxicity AT sameernazeeruddin modulatingthecatalyticactivityofampkhasneuroprotectiveeffectsagainstasynucleintoxicity AT grahamknott modulatingthecatalyticactivityofampkhasneuroprotectiveeffectsagainstasynucleintoxicity AT patrickaebischer modulatingthecatalyticactivityofampkhasneuroprotectiveeffectsagainstasynucleintoxicity AT bernardlschneider modulatingthecatalyticactivityofampkhasneuroprotectiveeffectsagainstasynucleintoxicity |
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