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Self-Perpetuating Structural States in Biology, Disease, and Genetics (2002) / Chapter Skim
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Chaperoning brain degeneration
Pages 31-35

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From page 31...
... A Drosophila Model for Human Neurodegenerative Disease To establish the fly as a model system for human neurodegeneration, we decided to express in the fly the normal form and a mutant disease form of the gene encoding spinocerebellar ataxia type 3, or MJD. We used a truncated form of the disease protein in these studies, as this protein had been shown to have effects when expressed in transgenic mice (14~.
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From page 32...
... This finding suggests that toxicity to the polyglutamine protein is sensitive to the levels of the Hsp70 family of molecular chaperones, with added Hsp70 preventing degeneration, whereas interference with endogenous chaperone activity promotes degeneration. We also investigated the role of the Hsp70 co-chaperone Hsp40 in protein pathogenicity, by creating transgenic flies that overexpress the fly counterpart of the human Hdjl class of molecular chaperone, dHdjl.
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From page 33...
... Chaperone Suppression of e-Synuclein Toxicity in a Drosophila Model for Parkinson's Disease The demonstration that Drosophila can be used to model a human neurodegenerative disease by directed expression of the respective human disease protein opened the possibility of modeling human neurodegenerative diseases other than polyglutamine diseases in the fly. Indeed, directed expression of or-synuclein, a component of Lewy bodies and mutated in familial forms of Parkinson's disease, causes adult-onset degeneration of dopaminergic neurons in Drosophila, thereby providing a model for Parkinson's disease (Fig.
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From page 34...
... Moreover, these studies in Drosophila for polyglutamine toxicity have been found to translate to mammalian models for polyglutamine toxicity. Up-regulation of Hsp70 in transgenic mice expressing the Ataxin-1 pathogenic poly~lutamine disease protein leads to protection against beEndogenous Chaperone Activity Plays a Role in c'-Synuclein Toxicity in Drosophila and Potentially also in Parkinson's Disease To ask whether endogenous chaperone levels may normally help protect against c~-synuclein toxicity, the dominant-negative form of Hsc4 was co-expressed with the disease protein.
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From page 35...
... However, this observation could be explained by cellular differences in the chaperone response to the specific protein in different tissues. With the ever-accelerating development of fly models for various human neurodegenerative diseases, and tremendous interest in such models for both standard genetic and pharmacological approaches, Drosophila may reveal new cures and treatments of relevance to human neurodegeneration, including polyglutamine and Parkinson's diseases.
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Key Terms

  • disease protein
  • dopaminergic neurons
  • chaperone activity
  • human neurodegenerative
  • pathogenic protein

  • eye structure
  • abnormal protein
  • lewy bodies
  • neurodegenerative disease
  • internal eye

  • disease process
  • neurodegenerative diseases
  • protein accumulations
  • pathogenic polyglutamine
  • endogenous chaperone

  • polyglutamine disease
  • human neurodegeneration
  • western immunoblot
  • human diseases
  • severe degeneration

  • polyglutamine diseases
  • human disease
  • nuclear inclusions
  • polyglutamine repeat
  • pathogenic actions

  • hughes medical
  • drosophila genetics
  • fundamental properties
  • medical institute
  • molecular chaperones


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