Conditional disruption of AMP kinase in dopaminergic neurons promotes Parkinson's disease-associated phenotypes in vivo

Emerging studies implicate energy dysregulation as an underlying trigger for Parkinson's disease (PD), suggesting that a better understanding of the molecular pathways governing energy homeostasis could help elucidate therapeutic targets for the disease. A critical cellular energy regulator is...

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Autores principales:	Liting Hang, Ziyin Wang, Aaron S.C. Foo, Geraldine W.Y. Goh, Huey Ching Choong, John Thundyil, Shengli Xu, Kong-Peng Lam, Kah-Leong Lim
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Parkinson's disease AMPK Mitochondria Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
Acceso en línea:	https://doaj.org/article/e681f29124b6458790dfeedd53c81d8a
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spelling	oai:doaj.org-article:e681f29124b6458790dfeedd53c81d8a2021-12-04T04:33:13ZConditional disruption of AMP kinase in dopaminergic neurons promotes Parkinson's disease-associated phenotypes in vivo1095-953X10.1016/j.nbd.2021.105560https://doaj.org/article/e681f29124b6458790dfeedd53c81d8a2021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S0969996121003090https://doaj.org/toc/1095-953XEmerging studies implicate energy dysregulation as an underlying trigger for Parkinson's disease (PD), suggesting that a better understanding of the molecular pathways governing energy homeostasis could help elucidate therapeutic targets for the disease. A critical cellular energy regulator is AMP kinase (AMPK), which we have previously shown to be protective in PD models. However, precisely how AMPK function impacts on dopaminergic neuronal survival and disease pathogenesis remains elusive. Here, we showed that Drosophila deficient in AMPK function exhibits PD-like features, including dopaminergic neuronal loss and climbing impairment that progress with age. We also created a tissue-specific AMPK-knockout mouse model where the catalytic subunits of AMPK are ablated in nigral dopaminergic neurons. Using this model, we demonstrated that loss of AMPK function promotes dopaminergic neurodegeneration and associated locomotor aberrations. Accompanying this is an apparent reduction in the number of mitochondria in the surviving AMPK-deficient nigral dopaminergic neurons, suggesting that an impairment in mitochondrial biogenesis may underlie the observed PD-associated phenotypes. Importantly, the loss of AMPK function enhances the susceptibility of nigral dopaminergic neurons in these mice to 6-hydroxydopamine-induced toxicity. Notably, we also found that AMPK activation is reduced in post-mortem PD brain samples. Taken together, these findings highlight the importance of neuronal energy homeostasis by AMPK in PD and position AMPK pathway as an attractive target for future therapeutic exploitation.Liting HangZiyin WangAaron S.C. FooGeraldine W.Y. GohHuey Ching ChoongJohn ThundyilShengli XuKong-Peng LamKah-Leong LimElsevierarticleParkinson's diseaseAMPKMitochondriaNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENNeurobiology of Disease, Vol 161, Iss , Pp 105560- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Parkinson's disease AMPK Mitochondria Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
spellingShingle	Parkinson's disease AMPK Mitochondria Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Liting Hang Ziyin Wang Aaron S.C. Foo Geraldine W.Y. Goh Huey Ching Choong John Thundyil Shengli Xu Kong-Peng Lam Kah-Leong Lim Conditional disruption of AMP kinase in dopaminergic neurons promotes Parkinson's disease-associated phenotypes in vivo
description	Emerging studies implicate energy dysregulation as an underlying trigger for Parkinson's disease (PD), suggesting that a better understanding of the molecular pathways governing energy homeostasis could help elucidate therapeutic targets for the disease. A critical cellular energy regulator is AMP kinase (AMPK), which we have previously shown to be protective in PD models. However, precisely how AMPK function impacts on dopaminergic neuronal survival and disease pathogenesis remains elusive. Here, we showed that Drosophila deficient in AMPK function exhibits PD-like features, including dopaminergic neuronal loss and climbing impairment that progress with age. We also created a tissue-specific AMPK-knockout mouse model where the catalytic subunits of AMPK are ablated in nigral dopaminergic neurons. Using this model, we demonstrated that loss of AMPK function promotes dopaminergic neurodegeneration and associated locomotor aberrations. Accompanying this is an apparent reduction in the number of mitochondria in the surviving AMPK-deficient nigral dopaminergic neurons, suggesting that an impairment in mitochondrial biogenesis may underlie the observed PD-associated phenotypes. Importantly, the loss of AMPK function enhances the susceptibility of nigral dopaminergic neurons in these mice to 6-hydroxydopamine-induced toxicity. Notably, we also found that AMPK activation is reduced in post-mortem PD brain samples. Taken together, these findings highlight the importance of neuronal energy homeostasis by AMPK in PD and position AMPK pathway as an attractive target for future therapeutic exploitation.
format	article
author	Liting Hang Ziyin Wang Aaron S.C. Foo Geraldine W.Y. Goh Huey Ching Choong John Thundyil Shengli Xu Kong-Peng Lam Kah-Leong Lim
author_facet	Liting Hang Ziyin Wang Aaron S.C. Foo Geraldine W.Y. Goh Huey Ching Choong John Thundyil Shengli Xu Kong-Peng Lam Kah-Leong Lim
author_sort	Liting Hang
title	Conditional disruption of AMP kinase in dopaminergic neurons promotes Parkinson's disease-associated phenotypes in vivo
title_short	Conditional disruption of AMP kinase in dopaminergic neurons promotes Parkinson's disease-associated phenotypes in vivo
title_full	Conditional disruption of AMP kinase in dopaminergic neurons promotes Parkinson's disease-associated phenotypes in vivo
title_fullStr	Conditional disruption of AMP kinase in dopaminergic neurons promotes Parkinson's disease-associated phenotypes in vivo
title_full_unstemmed	Conditional disruption of AMP kinase in dopaminergic neurons promotes Parkinson's disease-associated phenotypes in vivo
title_sort	conditional disruption of amp kinase in dopaminergic neurons promotes parkinson's disease-associated phenotypes in vivo
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/e681f29124b6458790dfeedd53c81d8a
work_keys_str_mv	AT litinghang conditionaldisruptionofampkinaseindopaminergicneuronspromotesparkinsonsdiseaseassociatedphenotypesinvivo AT ziyinwang conditionaldisruptionofampkinaseindopaminergicneuronspromotesparkinsonsdiseaseassociatedphenotypesinvivo AT aaronscfoo conditionaldisruptionofampkinaseindopaminergicneuronspromotesparkinsonsdiseaseassociatedphenotypesinvivo AT geraldinewygoh conditionaldisruptionofampkinaseindopaminergicneuronspromotesparkinsonsdiseaseassociatedphenotypesinvivo AT hueychingchoong conditionaldisruptionofampkinaseindopaminergicneuronspromotesparkinsonsdiseaseassociatedphenotypesinvivo AT johnthundyil conditionaldisruptionofampkinaseindopaminergicneuronspromotesparkinsonsdiseaseassociatedphenotypesinvivo AT shenglixu conditionaldisruptionofampkinaseindopaminergicneuronspromotesparkinsonsdiseaseassociatedphenotypesinvivo AT kongpenglam conditionaldisruptionofampkinaseindopaminergicneuronspromotesparkinsonsdiseaseassociatedphenotypesinvivo AT kahleonglim conditionaldisruptionofampkinaseindopaminergicneuronspromotesparkinsonsdiseaseassociatedphenotypesinvivo
_version_	1718373002715856896

Conditional disruption of AMP kinase in dopaminergic neurons promotes Parkinson's disease-associated phenotypes in vivo

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