Nuclear translocation of AMPK-a1 potentiates striatal neurodegeneration in Huntington's disease

Ju, Tz-Chuen; Lin, Jiun‐Tsai; Chang, Ching-Pang; Chang, W.S.C.; Kang, Jheng-Jie; Sun, Cheng‐Pu; Tao, Mi‐Hua; Tu, Pang‐Hsien; Chang, Chen; Dickson, Dennis W.; Chern, Yijuang

doi:10.1084/jem2088oia24

Cited by 17 publications

(27 citation statements)

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“…Interestingly, neuronal apoptosis was recently described in a model of Huntington's disease as dependent on nuclear accumulation of AMPK-a1. 38 In conclusion, our data suggest that FOXO3 activation represents a key step during bim-mediated excitotoxic neuronal death. The complex interplay between cellular bioenergetics, AMPK activation, and mTOR/AKT/FOXO3 signaling provides a molecular framework for cell fate decision making, preventing unwanted apoptosis activation during physiological AMPK activation or during conditions of mild bioenergetic stress.…”

Section: Discussionmentioning

confidence: 61%

Two-step activation of FOXO3 by AMPK generates a coherent feed-forward loop determining excitotoxic cell fate

et al. 2012

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Cerebral ischemia and excitotoxic injury induce transient or permanent bioenergetic failure, and may result in neuronal apoptosis or necrosis. We have previously shown that ATP depletion and activation of AMP-activated protein kinase (AMPK) during excitotoxic injury induces neuronal apoptosis by transcription of the pro-apoptotic BH3-only protein, Bim. AMPK, however, also exerts pro-survival functions in neurons. The molecular switches that determine these differential outcomes are not well understood. Using an approach combining biochemistry, single-cell imaging and computational modeling, we here demonstrate that excitotoxic injury activated the bim promoter in a FOXO3-dependent manner. The activation of AMPK reduced AKT activation, and led to dephosphorylation and nuclear translocation of FOXO3. Subsequent mutation studies indicated that bim gene activation during excitotoxic injury required direct FOXO3 phosphorylation by AMPK in the nucleus as a second activation step. Inhibition of this phosphorylation prevented Bim expression and protected neurons against excitotoxic and oxygen/glucose deprivation-induced injury. Systems analysis and computational modeling revealed that these two activation steps defined a coherent feed-forward loop; a network motif capable of filtering any effects of short-term AMPK activation on bim gene induction. This may prevent unwanted AMPK-mediated Bim expression and apoptosis during transient or physiological bioenergetic stress. Excitotoxicity has been implicated in the pathogenesis of cerebral ischemia and several neurodegenerative disorders, 1-3 and results from abnormal levels of the excitatory neurotransmitter glutamate (GLUT) in the synaptic cleft. [4][5][6]

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Section: Discussionmentioning

confidence: 61%

Two-step activation of FOXO3 by AMPK generates a coherent feed-forward loop determining excitotoxic cell fate

et al. 2012

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“…How AMPK signaling specificity relates to its subcellular location is not well understood. AMPK is generally considered a cytosolic protein with some indication that it traffics to the nucleus depending upon its active state (10,27). There is also evidence that AMPK can associate with subcellular membranes, including the plasma membrane, through myristoylation of its ␤-subunit.…”

Section: Discussionmentioning

confidence: 99%

N-cadherin coordinates AMP kinase-mediated lung vascular repair

Jian¹,

Liu

Li³

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…The major characteristic of HD is the selective loss of neurons in the neostriatum, nigrostriatal tract, and cortex, which leads to movement disorders, dementia, and eventual death. 79 Recent research showed that mitochondria and several key molecular players in energy homeostasis are altered during HD progression. Notably, mutated Htt (mHtt) forms aggregates on mitochondrial membranes.…”

Section: Ampk In Hdmentioning

confidence: 99%

“…82 Ju et al highlighted that the activation of AMPKα1 in striatal neurons is closely associated with mHtt-induced cell death. 79 The induction of neurotoxicity requires the nuclear translocation of AMPKα1 to suppress the expression of the survival gene Bcl2 in striatal neurons. 79 Furthermore, AMPK activation by AICAR in HD mice induces neuronal apoptotic activation and worsens motor function.…”

Section: Ampk In Hdmentioning

confidence: 99%

“…79 The induction of neurotoxicity requires the nuclear translocation of AMPKα1 to suppress the expression of the survival gene Bcl2 in striatal neurons. 79 Furthermore, AMPK activation by AICAR in HD mice induces neuronal apoptotic activation and worsens motor function. 79,81 The same research groups showed that the induction of cAMP/PKA signaling reduces AMPK activity, thus preventing the detrimental effect of AMPKα1 in the nuclei of striatal neurons.…”

Section: Ampk In Hdmentioning

confidence: 99%

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AMPK in the central nervous system: physiological roles and pathological implications

Rosso¹,

Fioramonti²,

Fracassi³

et al. 2016

RRB

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5′ AMP-activated protein kinase (AMPK) is considered the master metabolic regulator in all eukaryotes, as it maintains cellular energy homeostasis in a variety of tissues, including the brain. In humans, alterations in AMPK activity can lead to a wide spectrum of metabolic disorders. The relevance of this protein kinase in the pathogenesis of diabetes and metabolic syndrome is now well established. On the contrary, correlations between AMPK and brain physiopathology are still poorly characterized. The aim of this review is to summarize and discuss the current knowledge about the prospective involvement of AMPK in the onset and the progression of different neurological diseases.

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Nuclear translocation of AMPK-a1 potentiates striatal neurodegeneration in Huntington's disease

Cited by 17 publications

References 1 publication

Two-step activation of FOXO3 by AMPK generates a coherent feed-forward loop determining excitotoxic cell fate

Two-step activation of FOXO3 by AMPK generates a coherent feed-forward loop determining excitotoxic cell fate

N-cadherin coordinates AMP kinase-mediated lung vascular repair

AMPK in the central nervous system: physiological roles and pathological implications

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