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Citation
Hrizo, S.L., Palladino, M.J. (2010). Hsp70- and Hsp90-mediated proteasomal degradation underlies TPI(sugarkill) pathogenesis in Drosophila.  Neurobiol. Disease 40(3): 676--683.
FlyBase ID
FBrf0212050
Publication Type
Research paper
Abstract
Triosephosphate isomerase (TPI) deficiency is a severe glycolytic enzymopathy that causes progressive locomotor impairment and neurodegeneration, susceptibility to infection, and premature death. The recessive missense TPI(sugarkill) mutation in Drosophila melanogaster exhibits phenotypes analogous to human TPI deficiency such as progressive locomotor impairment, neurodegeneration, and reduced life span. We have shown that the TPI(sugarkill) protein is an active stable dimer; however, the mutant protein is turned over by the proteasome reducing cellular levels of this glycolytic enzyme. As proteasome function is often coupled with molecular chaperone activity, we hypothesized that TPI(sugarkill) is recognized by molecular chaperones that mediate the proteasomal degradation of the mutant protein. Coimmunoprecipitation data and analyses of TPI(sugarkill) turnover in animals with reduced or enhanced molecular chaperone activity indicate that both Hsp90 and Hsp70 are important for targeting TPI(sugarkill) for degradation. Furthermore, molecular chaperone and proteasome activity modified by pharmacological or genetic manipulations resulted in improved TPI(sugarkill) protein levels and rescue some but not all of the disease phenotypes suggesting that TPI deficiency pathology is complex. Overall, these data demonstrate a surprising role for Hsp70 and Hsp90 in the progression of neural dysfunction associated with TPI deficiency.
PubMed ID
PubMed Central ID
PMC2955819 (PMC) (EuropePMC)
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Secondary IDs
    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    Neurobiol. Disease
    Title
    Neurobiology of Disease
    Publication Year
    1994-
    ISBN/ISSN
    0969-9961
    Data From Reference
    Alleles (6)
    Genes (9)
    Human Disease Models (1)
    Physical Interactions (2)
    Transgenic Constructs (2)