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AMP Kinase Activation is Selectively Disrupted in the Ventral Midbrain of Mice Deficient in Parkin or PINK1 Expression

Parkinson’s disease (PD) is a prevalent neurodegenerative movement disorder that is characterized pathologically by the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) of the midbrain. Despite intensive research, the etiology of PD remains poorly understood...

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Autores principales: Hang, Liting, Thundyil, John, Goh, Geraldine W. Y., Lim, Kah-Leong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6394446/
https://www.ncbi.nlm.nih.gov/pubmed/30411223
http://dx.doi.org/10.1007/s12017-018-8517-7
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author Hang, Liting
Thundyil, John
Goh, Geraldine W. Y.
Lim, Kah-Leong
author_facet Hang, Liting
Thundyil, John
Goh, Geraldine W. Y.
Lim, Kah-Leong
author_sort Hang, Liting
collection PubMed
description Parkinson’s disease (PD) is a prevalent neurodegenerative movement disorder that is characterized pathologically by the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) of the midbrain. Despite intensive research, the etiology of PD remains poorly understood. Interestingly, recent studies have implicated neuronal energy dysregulation as one of the key perpetrators of the disease. Supporting this, we have recently demonstrated that pharmacological or genetic activation of AMP kinase (AMPK), a master regulator of cellular energy homeostasis, rescues the pathological phenotypes of Drosophila models of PD. However, little is known about the role of AMPK in the mammalian brain. As an initial attempt to clarify this, we examined the expression of AMPK in rodent brains and found that phospho-AMPK (pAMPK) is disproportionately distributed in the adult mouse brain, being high in the ventral midbrain where the SN resides and relatively lower in regions such as the cortex—reflecting perhaps the unique energy demands of midbrain DA neurons. Importantly, the physiologically higher level of midbrain pAMPK is significantly reduced in aged mice and also in Parkin-deficient mice; the loss of function of which in humans causes recessive Parkinsonism. Not surprisingly, the expression of PGC-1α, a downstream target of AMPK activity, and a key regulator of mitochondrial biogenesis, mirrors the expression pattern of pAMPK. Similar observations were made with PINK1-deficient mice. Finally, we showed that metformin administration restores the level of midbrain pAMPK and PGC-1α expression in Parkin-deficient mice. Taken together, our results suggest that the disruption of AMPK-PGC-1α axis in the brains of individuals with Parkin or PINK1 mutations may be a precipitating factor of PD, and that pharmacological AMPK activation may represent a neuroprotective strategy for the disease.
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spelling pubmed-63944462019-03-15 AMP Kinase Activation is Selectively Disrupted in the Ventral Midbrain of Mice Deficient in Parkin or PINK1 Expression Hang, Liting Thundyil, John Goh, Geraldine W. Y. Lim, Kah-Leong Neuromolecular Med Original Paper Parkinson’s disease (PD) is a prevalent neurodegenerative movement disorder that is characterized pathologically by the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) of the midbrain. Despite intensive research, the etiology of PD remains poorly understood. Interestingly, recent studies have implicated neuronal energy dysregulation as one of the key perpetrators of the disease. Supporting this, we have recently demonstrated that pharmacological or genetic activation of AMP kinase (AMPK), a master regulator of cellular energy homeostasis, rescues the pathological phenotypes of Drosophila models of PD. However, little is known about the role of AMPK in the mammalian brain. As an initial attempt to clarify this, we examined the expression of AMPK in rodent brains and found that phospho-AMPK (pAMPK) is disproportionately distributed in the adult mouse brain, being high in the ventral midbrain where the SN resides and relatively lower in regions such as the cortex—reflecting perhaps the unique energy demands of midbrain DA neurons. Importantly, the physiologically higher level of midbrain pAMPK is significantly reduced in aged mice and also in Parkin-deficient mice; the loss of function of which in humans causes recessive Parkinsonism. Not surprisingly, the expression of PGC-1α, a downstream target of AMPK activity, and a key regulator of mitochondrial biogenesis, mirrors the expression pattern of pAMPK. Similar observations were made with PINK1-deficient mice. Finally, we showed that metformin administration restores the level of midbrain pAMPK and PGC-1α expression in Parkin-deficient mice. Taken together, our results suggest that the disruption of AMPK-PGC-1α axis in the brains of individuals with Parkin or PINK1 mutations may be a precipitating factor of PD, and that pharmacological AMPK activation may represent a neuroprotective strategy for the disease. Springer US 2018-11-08 2019 /pmc/articles/PMC6394446/ /pubmed/30411223 http://dx.doi.org/10.1007/s12017-018-8517-7 Text en © The Author(s) 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Original Paper
Hang, Liting
Thundyil, John
Goh, Geraldine W. Y.
Lim, Kah-Leong
AMP Kinase Activation is Selectively Disrupted in the Ventral Midbrain of Mice Deficient in Parkin or PINK1 Expression
title AMP Kinase Activation is Selectively Disrupted in the Ventral Midbrain of Mice Deficient in Parkin or PINK1 Expression
title_full AMP Kinase Activation is Selectively Disrupted in the Ventral Midbrain of Mice Deficient in Parkin or PINK1 Expression
title_fullStr AMP Kinase Activation is Selectively Disrupted in the Ventral Midbrain of Mice Deficient in Parkin or PINK1 Expression
title_full_unstemmed AMP Kinase Activation is Selectively Disrupted in the Ventral Midbrain of Mice Deficient in Parkin or PINK1 Expression
title_short AMP Kinase Activation is Selectively Disrupted in the Ventral Midbrain of Mice Deficient in Parkin or PINK1 Expression
title_sort amp kinase activation is selectively disrupted in the ventral midbrain of mice deficient in parkin or pink1 expression
topic Original Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6394446/
https://www.ncbi.nlm.nih.gov/pubmed/30411223
http://dx.doi.org/10.1007/s12017-018-8517-7
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