PMID:21768291

Citation	Ju, TC, Chen, HM, Lin, JT, Chang, CP, Chang, WC, Kang, JJ, Sun, CP, Tao, MH, Tu, PH, Chang, C, Dickson, DW and Chern, Y (2011) Nuclear translocation of AMPK-alpha1 potentiates striatal neurodegeneration in Huntington's disease. J. Cell Biol. 194:209-27
Abstract	Adenosine monophosphate-activated protein kinase (AMPK) is a major energy sensor that maintains cellular energy homeostasis. Huntington's disease (HD) is a neurodegenerative disorder caused by the expansion of CAG repeats in the huntingtin (Htt) gene. In this paper, we report that activation of the α1 isoform of AMPK (AMPK-α1) occurred in striatal neurons of humans and mice with HD. Overactivation of AMPK in the striatum caused brain atrophy, facilitated neuronal loss, and increased formation of Htt aggregates in a transgenic mouse model (R6/2) of HD. Such nuclear accumulation of AMPK-α1 was activity dependent. Prevention of nuclear translocation or inactivation of AMPK-α1 ameliorated cell death and down-regulation of Bcl2 caused by mutant Htt (mHtt). Conversely, enhanced expression of Bcl2 protected striatal cells from the toxicity evoked by mHtt and AMPK overactivation. These data demonstrate that aberrant activation of AMPK-α1 in the nuclei of striatal cells represents a new toxic pathway induced by mHtt.
Links	PubMed PMC3144412 Online version:10.1083/jcb.201105010
Keywords	AMP-Activated Protein Kinases/metabolism; Active Transport, Cell Nucleus; Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism; Cell Nucleus/metabolism; Cells, Cultured; Humans; Huntingtin Protein; Huntington Disease/enzymology; Huntington Disease/metabolism; Mice; Mice, Transgenic; Mutation; Neostriatum/metabolism; Neostriatum/pathology; Nerve Degeneration/enzymology; Nerve Degeneration/metabolism; Nerve Tissue Proteins/genetics; Nerve Tissue Proteins/metabolism; Nuclear Proteins/genetics; Nuclear Proteins/metabolism; Proto-Oncogene Proteins c-bcl-2/metabolism
edit table

Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:HD	involved_in	GO:1905289: regulation of CAMKK-AMPK signaling cascade	ECO:0000315: mutant phenotype evidence used in manual assertion		P	occurs_in:(UBERON:0002435)	Seeded From UniProt	complete
HUMAN:HD	involved_in	GO:2000479: regulation of cAMP-dependent protein kinase activity	ECO:0000315: mutant phenotype evidence used in manual assertion		P	has_input:(UniProtKB:Q13131) occurs_in:(UBERON:0002435)	Seeded From UniProt	complete
MOUSE:HD	involved_in	GO:1900180: regulation of protein localization to nucleus	ECO:0000315: mutant phenotype evidence used in manual assertion		P	occurs_in:(UBERON:0002435) regulates:(GO:0051402)	Seeded From UniProt	complete
MOUSE:HD	involved_in	GO:0043523: regulation of neuron apoptotic process	ECO:0000315: mutant phenotype evidence used in manual assertion		P	occurs_in:(UBERON:0002435)	Seeded From UniProt	complete
MOUSE:HD	involved_in	GO:2000479: regulation of cAMP-dependent protein kinase activity	ECO:0000315: mutant phenotype evidence used in manual assertion		P	has_input:(UniProtKB:Q5EG47) occurs_in:(UBERON:0002435)	Seeded From UniProt	complete
MOUSE:HD	involved_in	GO:0010468: regulation of gene expression	ECO:0000315: mutant phenotype evidence used in manual assertion		P	occurs_in:(UBERON:0002435) regulates_expression_of:(UniProtKB:P10417) regulates:(GO:0051402)	Seeded From UniProt	complete
HUMAN:AAPK1	involved_in	GO:0070050: neuron cellular homeostasis	ECO:0000316: genetic interaction evidence used in manual assertion	UniProtKB:P42858	P	occurs_in:(UBERON:0002435)	Seeded From UniProt	complete
HUMAN:AAPK1	part_of	GO:0005737: cytoplasm	ECO:0000314: direct assay evidence used in manual assertion		C	part_of:(UBERON:0001873)|part_of:(UBERON:0001870)	Seeded From UniProt	complete
MOUSE:AAPK1	part_of	GO:0005737: cytoplasm	ECO:0000314: direct assay evidence used in manual assertion		C	part_of:(UBERON:0002435)	Seeded From UniProt	complete
HUMAN:HD	involved_in	GO:2000479: regulation of cAMP-dependent protein kinase activity	ECO:0000315: mutant phenotype evidence used in manual assertion		P	has_regulation_target:(UniProtKB:Q13131) occurs_in:(UBERON:0002435)	Seeded From UniProt	complete
HUMAN:HD	involved_in	GO:1905289: regulation of CAMKK-AMPK signaling cascade	ECO:0000315: mutant phenotype evidence used in manual assertion		P	occurs_in:(UBERON:0002435)	Seeded From UniProt	complete
MOUSE:AAPK1	part_of	GO:0005737: cytoplasm	ECO:0000314: direct assay evidence used in manual assertion		C	part_of:(UBERON:0002435)	Seeded From UniProt	complete
HUMAN:AAPK2	part_of	GO:0005634: nucleus	ECO:0000304: author statement supported by traceable reference used in manual assertion		C		Seeded From UniProt	complete
HUMAN:AAPK1	involved_in	GO:0070050: neuron cellular homeostasis	ECO:0000316: genetic interaction evidence used in manual assertion	UniProtKB:P42858	P	occurs_in:(UBERON:0002435)	Seeded From UniProt	complete
HUMAN:AAPK1	involved_in	GO:0061744: motor behavior	ECO:0000316: genetic interaction evidence used in manual assertion	UniProtKB:P42858	P		Seeded From UniProt	complete
HUMAN:AAPK1	part_of	GO:0005737: cytoplasm	ECO:0000314: direct assay evidence used in manual assertion		C	part_of:(UBERON:0001873)|part_of:(UBERON:0001870)	Seeded From UniProt	complete
HUMAN:AAPK1	involved_in	GO:0097009: energy homeostasis	ECO:0000304: author statement supported by traceable reference used in manual assertion		P		Seeded From UniProt	complete
HUMAN:AAPK1	part_of	GO:0031588: nucleotide-activated protein kinase complex	ECO:0000304: author statement supported by traceable reference used in manual assertion		C		Seeded From UniProt	complete
HUMAN:AAPK1	involved_in	GO:0061762: CAMKK-AMPK signaling cascade	ECO:0000304: author statement supported by traceable reference used in manual assertion		P		Seeded From UniProt	complete
HUMAN:AAPK1	enables	GO:0004679: AMP-activated protein kinase activity	ECO:0000304: author statement supported by traceable reference used in manual assertion		F		Seeded From UniProt	complete

References

See Help:References for how to manage references in GONUTS.