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PMID: 18299572 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Hypothalamic neurodegeneration and adult-onset obesity in mice lacking the Ubb polyubiquitin gene.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 105 ·No. 10 ·2008-03-11 ·Pages 4016-21

Ryu KY, Garza JC, Lu XY, Barsh GS, Kopito RR

Abstract

Nearly all neurodegenerative diseases are associated with abnormal accumulation of ubiquitin (Ub) conjugates within neuronal inclusion bodies. To directly test the hypothesis that depletion of cellular Ub is sufficient to cause neurodegeneration, we have disrupted Ubb, one of four genes that supply Ub in the mouse. Here, we report that loss of Ubb led to a progressive degenerative disorder affecting neurons within the arcuate nucleus of the hypothalamus. This neurodegenerative cytopathology was accompanied by impaired hypothalamic control of energy balance and adult-onset obesity. Ubb was highly expressed in vulnerable hypothalamic neurons and total Ub levels were selectively reduced in the hypothalamus of Ubb-null mice. These findings demonstrate that maintenance of adequate supplies of cellular Ub is essential for neuronal survival and establish that decreased Ub availability is sufficient to cause neuronal dysfunction and death.

MeSH Terms
Animals Animals, Newborn Body Composition Body Weight Energy Metabolism Feeding Behavior Gene Expression Regulation Hypothalamus/pathology Mice Nerve Degeneration/complications Neuropeptides/genetics,metabolism Obesity/complications Polyubiquitin/genetics Ubiquitin/deficiency,genetics,metabolism
Chemicals
Neuropeptides Ubb protein, mouse Ubiquitin Polyubiquitin
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Ryu Kwon-Yul
Department of Biological Sciences, Bio-X Program, and Department of Genetics, Stanford University, Stanford, CA 94305, USA.
Garza Jacob C
Lu Xin-Yun
Barsh Gregory S
Kopito Ron R
References (43)
43 references, click to expand
  1. Parkin and Parkinson's disease.
    Curr Opin Neurol. 2001 Aug;14(4):477-82 PMID: 11470964
  2. The yeast polyubiquitin gene is essential for resistance to high temperatures, starvation, and other stresses.
    Cell. 1987 Mar 27;48(6):1035-46 PMID: 3030556
  3. Nerve growth factor (NGF) induces increase in multi-ubiquitin chains and concomitant decrease in free ubiquitin in nuclei of PC12h.
    Neurosci Res. 1996 Dec;26(4):349-55 PMID: 9004273
  4. The tails of ubiquitin precursors are ribosomal proteins whose fusion to ubiquitin facilitates ribosome biogenesis.
    Nature. 1989 Mar 30;338(6214):394-401 PMID: 2538753
  5. Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate.
    Science. 1969 May 9;164(3880):719-21 PMID: 5778021
  6. Deubiquitinating enzymes: a new class of biological regulators.
    Crit Rev Biochem Mol Biol. 1998;33(5):337-52 PMID: 9827704
  7. Leptin and the regulation of body weight in mammals.
    Nature. 1998 Oct 22;395(6704):763-70 PMID: 9796811
  8. The human ubiquitin-52 amino acid fusion protein gene shares several structural features with mammalian ribosomal protein genes.
    Nucleic Acids Res. 1991 Mar 11;19(5):1035-40 PMID: 1850507
  9. Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin.
    Nat Med. 1999 Sep;5(9):1066-70 PMID: 10470087
  10. Axon pruning during Drosophila metamorphosis: evidence for local degeneration and requirement of the ubiquitin-proteasome system.
    Neuron. 2003 Jun 19;38(6):871-85 PMID: 12818174
  11. Loss of Usp14 results in reduced levels of ubiquitin in ataxia mice.
    J Neurochem. 2005 Nov;95(3):724-31 PMID: 16190881
  12. Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice.
    Diabetologia. 1978 Mar;14(3):141-8 PMID: 350680
  13. The ubiquitin system.
    Annu Rev Biochem. 1998;67:425-79 PMID: 9759494
  14. Ubiquitin-dependent protein degradation.
    Annu Rev Genet. 1996;30:405-39 PMID: 8982460
  15. The human ubiquitin multigene family: some genes contain multiple directly repeated ubiquitin coding sequences.
    EMBO J. 1985 Mar;4(3):755-9 PMID: 2988935
  16. Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass.
    Nat Genet. 2000 Sep;26(1):97-102 PMID: 10973258
  17. Ability of ubiquitin radioimmunoassay to discriminate between monoubiquitin and multi-ubiquitin chains.
    Biochim Biophys Acta. 1996 Aug 13;1290(3):282-8 PMID: 8765132
  18. Global changes to the ubiquitin system in Huntington's disease.
    Nature. 2007 Aug 9;448(7154):704-8 PMID: 17687326
  19. Identification of the long ubiquitin extension as ribosomal protein S27a.
    Nature. 1989 Mar 30;338(6214):438-40 PMID: 2538756
  20. Nucleotide sequence analysis of a cDNA encoding human ubiquitin reveals that ubiquitin is synthesized as a precursor.
    J Biol Chem. 1985 Jun 25;260(12):7609-13 PMID: 2581967
  21. Ubiquitin is a common factor in intermediate filament inclusion bodies of diverse type in man, including those of Parkinson's disease, Pick's disease, and Alzheimer's disease, as well as Rosenthal fibres in cerebellar astrocytomas, cytoplasmic bodies in muscle, and mallory bodies in alcoholic liver disease.
    J Pathol. 1988 May;155(1):9-15 PMID: 2837558
  22. Ubiquitin depletion as a key mediator of toxicity by translational inhibitors.
    Mol Cell Biol. 2003 Dec;23(24):9251-61 PMID: 14645527
  23. Disruption of neural signal transducer and activator of transcription 3 causes obesity, diabetes, infertility, and thermal dysregulation.
    Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4661-6 PMID: 15070774
  24. Diurnal rhythm of agouti-related protein and its relation to corticosterone and food intake.
    Endocrinology. 2002 Oct;143(10):3905-15 PMID: 12239102
  25. A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse.
    Endocrinology. 2000 Sep;141(9):3518-21 PMID: 10965927
  26. The mouse polyubiquitin gene UbC is essential for fetal liver development, cell-cycle progression and stress tolerance.
    EMBO J. 2007 Jun 6;26(11):2693-706 PMID: 17491588
  27. Interaction between alpha-melanocyte-stimulating hormone and corticotropin-releasing hormone in the regulation of feeding and hypothalamo-pituitary-adrenal responses.
    J Neurosci. 2003 Aug 27;23(21):7863-72 PMID: 12944516
  28. Ubiquitin carboxy-terminal hydrolase L1 binds to and stabilizes monoubiquitin in neuron.
    Hum Mol Genet. 2003 Aug 15;12(16):1945-58 PMID: 12913066
  29. The mouse polyubiquitin gene Ubb is essential for meiotic progression.
    Mol Cell Biol. 2008 Feb;28(3):1136-46 PMID: 18070917
  30. Synapse formation and plasticity: recent insights from the perspective of the ubiquitin proteasome system.
    Curr Opin Neurobiol. 2006 Feb;16(1):90-4 PMID: 16427269
  31. Using deubiquitylating enzymes as research tools.
    Methods Enzymol. 2005;398:540-54 PMID: 16275357
  32. Effects of hypothalamic neurodegeneration on energy balance.
    PLoS Biol. 2005 Dec;3(12):e415 PMID: 16296893
  33. The human ubiquitin gene family: structure of a gene and pseudogenes from the Ub B subfamily.
    Nucleic Acids Res. 1987 Jan 26;15(2):443-63 PMID: 3029682
  34. PI3K integrates the action of insulin and leptin on hypothalamic neurons.
    J Clin Invest. 2005 Apr;115(4):951-8 PMID: 15761497
  35. Modern science versus the stigma of obesity.
    Nat Med. 2004 Jun;10(6):563-9 PMID: 15170194
  36. An efficient system for high-level expression and easy purification of authentic recombinant proteins.
    Protein Sci. 2004 May;13(5):1331-9 PMID: 15096636
  37. The melanocortinergic pathway is rapidly recruited by emotional stress and contributes to stress-induced anorexia and anxiety-like behavior.
    Endocrinology. 2007 Nov;148(11):5531-40 PMID: 17673512
  38. The yeast ubiquitin genes: a family of natural gene fusions.
    EMBO J. 1987 May;6(5):1429-39 PMID: 3038523
  39. The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson's disease susceptibility.
    Cell. 2002 Oct 18;111(2):209-18 PMID: 12408865
  40. Ubiquitin is detected in neurofibrillary tangles and senile plaque neurites of Alzheimer disease brains.
    Proc Natl Acad Sci U S A. 1987 May;84(9):3033-6 PMID: 3033674
  41. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein.
    Science. 1997 Oct 3;278(5335):135-8 PMID: 9311920
  42. Ubiquitin-specific protease 2 as a tool for quantification of total ubiquitin levels in biological specimens.
    Anal Biochem. 2006 Jun 1;353(1):153-5 PMID: 16643835
  43. Overexpression of Agrt leads to obesity in transgenic mice.
    Nat Genet. 1997 Nov;17(3):273-4 PMID: 9354787
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.0800096105
Published
2008-03-11
Epub
2008-00-25
Pages
4016-21
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC2268782
Subset
IM
Grants
NIMH NIH HHS · R01 MH073844-05 · United States
NIMH NIH HHS · R01 MH073844 · United States
NIMH NIH HHS · R01 MH076929-02 · United States
NIMH NIH HHS · R01 MH076929-04 · United States
NIMH NIH HHS · R01 MH073844-04 · United States
NIMH NIH HHS · R01 MH076929-01A1 · United States
NIMH NIH HHS · R01 MH076929 · United States
NIMH NIH HHS · R01 MH073844-03 · United States
NIMH NIH HHS · R01 MH073844-01A2 · United States
NIMH NIH HHS · R01 MH076929-05 · United States
NIMH NIH HHS · R01 MH073844-02 · United States
NIMH NIH HHS · R01 MH076929-03 · United States
External Links
PubMed source DOI: 10.1073/pnas.0800096105 PMC Full Text View journal details
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