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PMID:21768291

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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

Significance

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

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

Notes

See also

References

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