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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Published in | Neurobiology of disease Vol. 161; p. 105560 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
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01.12.2021
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Abstract | 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.
•AMPK-deficient flies and mice exhibit Parkinson's disease-like phenotypes•Cells ablated of AMPK expression show reduced mitochondrial number and PGC-1α levels•AMPK-deficient mice are more susceptible to 6-OHDA-induced neurotoxicity•AMPK activity is apparently compromised in post-mortem PD brain samples•AMPK deficiency may underlie PD pathogenesis |
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AbstractList | 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. 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. •AMPK-deficient flies and mice exhibit Parkinson's disease-like phenotypes•Cells ablated of AMPK expression show reduced mitochondrial number and PGC-1α levels•AMPK-deficient mice are more susceptible to 6-OHDA-induced neurotoxicity•AMPK activity is apparently compromised in post-mortem PD brain samples•AMPK deficiency may underlie PD pathogenesis |
ArticleNumber | 105560 |
Author | Thundyil, John Xu, Shengli Goh, Geraldine W.Y. Lim, Kah-Leong Wang, Ziyin Choong, Huey Ching Foo, Aaron S.C. Hang, Liting Lam, Kong-Peng |
Author_xml | – sequence: 1 givenname: Liting surname: Hang fullname: Hang, Liting organization: Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore – sequence: 2 givenname: Ziyin surname: Wang fullname: Wang, Ziyin organization: Department of Research, National Neuroscience Institute, Singapore – sequence: 3 givenname: Aaron S.C. surname: Foo fullname: Foo, Aaron S.C. organization: Department of Physiology, National University of Singapore, Singapore – sequence: 4 givenname: Geraldine W.Y. surname: Goh fullname: Goh, Geraldine W.Y. organization: Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore – sequence: 5 givenname: Huey Ching surname: Choong fullname: Choong, Huey Ching organization: Department of Research, National Neuroscience Institute, Singapore – sequence: 6 givenname: John surname: Thundyil fullname: Thundyil, John organization: Department of Research, National Neuroscience Institute, Singapore – sequence: 7 givenname: Shengli surname: Xu fullname: Xu, Shengli organization: Department of Physiology, National University of Singapore, Singapore – sequence: 8 givenname: Kong-Peng surname: Lam fullname: Lam, Kong-Peng organization: Department of Microbiology & Immunology, National University of Singapore, Singapore – sequence: 9 givenname: Kah-Leong surname: Lim fullname: Lim, Kah-Leong email: kahleong.lim@ntu.edu.sg organization: Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/34767944$$D View this record in MEDLINE/PubMed |
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Keywords | ACC Parkinson's disease cKO SNpc 6-OHDA PGC-1α MFF Drp1 Mitochondria PINK1 Mfn Opa1 PD TH TOM20 AMPK mROS DA WT |
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SubjectTerms | Adenylate Kinase - genetics Adenylate Kinase - metabolism AMPK Animals Dopaminergic Neurons - metabolism Mice Mitochondria Parkinson Disease - metabolism Parkinson's disease Phenotype Substantia Nigra - metabolism |
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Title | Conditional disruption of AMP kinase in dopaminergic neurons promotes Parkinson's disease-associated phenotypes in vivo |
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