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
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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