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Modulating the catalytic activity of AMPK has neuroprotective effects against ?-synuclein toxicity.

ABSTRACT: 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.Here, we overexpress various genetic variants of the catalytic AMPK? subunit to determine how AMPK activity affects the survival and function of neurons overexpressing human ?-synuclein in vivo.Both AMPK?1 and ?2 subunits have neuroprotective effects against human ?-synuclein toxicity in nigral dopaminergic neurons. Remarkably, a modified variant of AMPK?1 (T172D?1) with constitutive low activity most effectively prevents the loss of dopamine neurons, as well as the motor impairments caused by ?-synuclein accumulation. In the striatum, T172D?1 decreases the formation of dystrophic axons, which contain aggregated ?-synuclein. In primary cortical neurons, overexpression of human ?-synuclein perturbs mitochondrial and lysosomal activities. Co-expressing AMPK? with ?-synuclein induces compensatory changes, which limit the accumulation of lysosomal material and increase the mitochondrial mass.Together, these results indicate that modulating AMPK activity can mitigate ?-synuclein toxicity in nigral dopamine neurons, which may have implications for the development of neuroprotective treatments against PD.

SUBMITTER: Bobela W

PROVIDER: S-EPMC5670705 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Modulating the catalytic activity of AMPK has neuroprotective effects against α-synuclein toxicity.

Bobela Wojciech W Nazeeruddin Sameer S Knott Graham G Aebischer Patrick P Schneider Bernard L BL

Molecular neurodegeneration 20171103 1

<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>Both AMPKα1 ...[more]

PMID: 29100525

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Project description:Angong Niuhuang Wan (AGNHW) is a classic prescription in traditional Chinese medicine (TCM) used for stroke treatment, but its efficacies remain to be confirmed. With its arsenic- and mercury-containing materials, the application of AGNHW raises great safety concerns. Herein, we aim to explore the neuropharmacological effects against cerebral ischemia-reperfusion injury and evaluate the toxicological effects of AGNHW for better use. Male SD rats were subjected to 2 h of middle cerebral artery occlusion (MCAO) and following 22 h of reperfusion. AGNHW (257 mg/kg, 1× AGNHW) were orally administered for pharmacological effects and 257, 514, and 1,028 mg/kg (equivalent to 1×, 2×, 4× AGNHW) were used for the toxicological study. The results revealed that AGNHW treatment reduced the infarct size and protected the blood-brain barrier (BBB) integrity in the MCAO rat ischemic stroke model. AGNHW treatment up-regulated bcl-2 expression and down-regulated the expressions of Bax, p47phox, inducible nitric oxide synthase (iNOS), and 3-nitrotyrosine (3-NT), and inhibited the expressions and activities of matrix metalloproteinase-2 (MMP-2), MMP-9, and reserved tight junction protein zonula occludens-1 (ZO-1) and claudin-5 in the ischemic brains. These results indicated that the neuroprotective mechanisms of AGNHW could be associated with its antioxidant properties by inhibiting oxidative/nitrative stress-mediated MMP activation and protecting tight junction proteins in the ischemic brains. Administration of 1× AGNHW for 7 days would not induce the accumulation of mercury in blood, liver, and kidney at day 14. Administration of 2× AGNHW and 4× AGNHW for 7 days increased the level of mercury in the kidney. For arsenic level, administration of 1× AGNHW for 7 days would increase the level of arsenic in the liver and blood without increase of arsenic in the kidney at day 14. Administration of 2× AGNHW and 4× AGNHW for 7 days would further increase the level of arsenic in the liver and blood. There is no influence on body weight, organ index, histological structures, and renal and liver functions. These results suggest that short-term treatment of AGNHW within 1 week should be safe and has neuroprotective effects against cerebral ischemia-reperfusion injury.

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Modulating the catalytic activity of AMPK has neuroprotective effects against ?-synuclein toxicity.

Publications

Modulating the catalytic activity of AMPK has neuroprotective effects against α-synuclein toxicity.

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