Compartmentalization of superoxide dismutase 1 (SOD1G93A) aggregates determines their toxicity.

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  • Author(s): Weisberg SJ;Weisberg SJ; Lyakhovetsky R; Werdiger AC; Gitler AD; Soen Y; Kaganovich D
  • Source:
    Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2012 Sep 25; Vol. 109 (39), pp. 15811-6. Date of Electronic Publication: 2012 Sep 11.
  • Publication Type:
    Journal Article; Research Support, Non-U.S. Gov't
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, DC : National Academy of Sciences
    • Subject Terms:
      Protein Folding*; HSP70 Heat-Shock Proteins/*metabolism ; Superoxide Dismutase/*metabolism; Amyotrophic Lateral Sclerosis/genetics ; Amyotrophic Lateral Sclerosis/metabolism ; Cell Line ; Cell Survival ; HSP70 Heat-Shock Proteins/genetics ; Humans ; Inclusion Bodies/genetics ; Inclusion Bodies/metabolism ; Proteasome Endopeptidase Complex ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1
    • Abstract:
      Neurodegenerative diseases constitute a class of illnesses marked by pathological protein aggregation in the brains of affected individuals. Although these disorders are invariably characterized by the degeneration of highly specific subpopulations of neurons, protein aggregation occurs in all cells, which indicates that toxicity arises only in particular cell biological contexts. Aggregation-associated disorders are unified by a common cell biological feature: the deposition of the culprit proteins in inclusion bodies. The precise function of these inclusions remains unclear. The starting point for uncovering the origins of disease pathology must therefore be a thorough understanding of the general cell biological function of inclusions and their potential role in modulating the consequences of aggregation. Here, we show that in human cells certain aggregate inclusions are active compartments. We find that toxic aggregates localize to one of these compartments, the juxtanuclear quality control compartment (JUNQ), and interfere with its quality control function. The accumulation of SOD1G93A aggregates sequesters Hsp70, preventing the delivery of misfolded proteins to the proteasome. Preventing the accumulation of SOD1G93A in the JUNQ by enhancing its sequestration in an insoluble inclusion reduces the harmful effects of aggregation on cell viability.
    • References:
      Brain Res. 2012 Jun 26;1462:61-80. (PMID: 22445064)
      Neuropharmacology. 2011 Jun;60(7-8):1187-92. (PMID: 21044641)
      Chem Biol. 2006 Nov;13(11):1217-26. (PMID: 17114003)
      Neurosci Lett. 2009 Jul 17;458(2):70-4. (PMID: 19379791)
      Neuron. 2001 Jan;29(1):15-32. (PMID: 11182078)
      Cold Spring Harb Perspect Biol. 2011 Oct 01;3(10):a007500. (PMID: 21844169)
      Nature. 2004 Oct 14;431(7010):805-10. (PMID: 15483602)
      Mol Biol Cell. 2011 Sep;22(18):3277-88. (PMID: 21775628)
      Nature. 2008 Aug 28;454(7208):1088-95. (PMID: 18756251)
      Science. 2006 Sep 15;313(5793):1604-10. (PMID: 16902091)
      Science. 2004 Jun 18;304(5678):1793-7. (PMID: 15155912)
      FEBS Lett. 2012 Jan 2;586(1):7-12. (PMID: 22119730)
      Annu Rev Biochem. 2006;75:333-66. (PMID: 16756495)
      Genes Dev. 2008 Jun 1;22(11):1427-38. (PMID: 18519635)
      Cell. 2005 Jun 3;121(5):739-48. (PMID: 15935760)
      PLoS Biol. 2006 Dec;4(12):e417. (PMID: 17147470)
      Proc Natl Acad Sci U S A. 2008 May 20;105(20):7206-11. (PMID: 18480252)
      Cell Cycle. 2009 Jun 1;8(11):1668-74. (PMID: 19411847)
      Curr Opin Struct Biol. 2011 Feb;21(1):32-41. (PMID: 21112769)
      Nat Genet. 1999 Dec;23(4):425-8. (PMID: 10581028)
      J Biol Chem. 2006 Feb 17;281(7):4477-85. (PMID: 16371362)
      Nat Neurosci. 2001 Sep;4(9):887-93. (PMID: 11528419)
      Physiol Rev. 2009 Oct;89(4):1105-52. (PMID: 19789378)
      Nat Rev Mol Cell Biol. 2010 Nov;11(11):777-88. (PMID: 20944667)
      J Biol Chem. 2008 Oct 10;283(41):27575-27584. (PMID: 18635553)
      J Neurosci. 2007 Nov 28;27(48):13173-80. (PMID: 18045911)
      J Cell Biol. 2005 Oct 10;171(1):75-85. (PMID: 16216923)
      J Biol Chem. 2002 May 3;277(18):15923-31. (PMID: 11854284)
      Nat Rev Neurosci. 2008 Oct;9(10):759-67. (PMID: 18769445)
      Trends Cell Biol. 2000 Dec;10(12):524-30. (PMID: 11121744)
      J Biol Chem. 2002 Dec 6;277(49):47358-65. (PMID: 12351637)
      FEBS Lett. 2011 Jan 21;585(2):381-4. (PMID: 21176779)
      Methods Enzymol. 2005;399:490-511. (PMID: 16338378)
      PLoS Genet. 2009 Jan;5(1):e1000350. (PMID: 19165329)
      Nat Cell Biol. 2005 Aug;7(8):736-41. (PMID: 16056264)
      Annu Rev Biochem. 1998;67:425-79. (PMID: 9759494)
    • Accession Number:
      0 (HSP70 Heat-Shock Proteins)
      0 (SOD1 protein, human)
      EC 1.15.1.1 (SOD1 G93A protein)
      EC 1.15.1.1 (Superoxide Dismutase)
      EC 1.15.1.1 (Superoxide Dismutase-1)
      EC 3.4.25.1 (Proteasome Endopeptidase Complex)
    • Publication Date:
      Date Created: 20120913 Date Completed: 20121205 Latest Revision: 20211021
    • Publication Date:
      20231215
    • Accession Number:
      PMC3465386
    • Accession Number:
      10.1073/pnas.1205829109
    • Accession Number:
      22967507