AMP Kinase Activation is Selectively Disrupted in the Ventral Midbrain of Mice Deficient in Parkin or PINK1 Expression
Autor: | Kah-Leong Lim, Liting Hang, Geraldine W.Y. Goh, John Thundyil |
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Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Male Aging Parkinson's disease Drug Evaluation Preclinical PGC-1α Parkin Mice 0302 clinical medicine Mesencephalon Phosphorylation Mice Knockout Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Metformin Cell biology Mitochondria Neurology Organ Specificity Molecular Medicine Ubiquitin-Protein Ligases AMP kinase Substantia nigra PINK1 Nerve Tissue Proteins Biology Midbrain 03 medical and health sciences Cellular and Molecular Neuroscience medicine Animals Pars Compacta Original Paper Pars compacta Dopaminergic Neurons Adenylate Kinase AMPK medicine.disease Enzyme Activation Mice Inbred C57BL 030104 developmental biology Mitochondrial biogenesis Gene Expression Regulation Parkinson’s disease Energy Metabolism Protein Kinases Protein Processing Post-Translational 030217 neurology & neurosurgery Parkinson Disease Associated Proteins |
Zdroj: | Neuromolecular Medicine |
ISSN: | 1559-1174 |
Popis: | 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. |
Databáze: | OpenAIRE |
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