The Heat Shock Response Is Modulated by and Interferes with Toxic Effects of Scrapie Prion Protein and Amyloid β*
| Autor: | Jörg Tatzelt, Mark R. Wilson, Ulrike K. Resenberger, Gerd Multhaup, Veronika Müller, Michael Baier, Konstanze F. Winklhofer, Lisa M. Munter |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
genetics [Cell Membrane]
genetics [HSP72 Heat-Shock Proteins] PrPSc Proteins animal diseases metabolism [Amyloid beta-Peptides] HSP72 Heat-Shock Proteins CHO Cells Biology Biochemistry metabolism [Cell Membrane] Cricetulus Heat shock protein Cricetinae CLU protein human genetics [Amyloid beta-Peptides] Animals Humans Heat shock Molecular Biology Amyloid beta-Peptides Clusterin Cell Membrane Molecular Bases of Disease Cell Biology genetics [PrPSc Proteins] Molecular biology nervous system diseases metabolism [HSP72 Heat-Shock Proteins] metabolism [Clusterin] Proteostasis Proteotoxicity Chaperone (protein) ddc:540 metabolism [PrPSc Proteins] biology.protein Ectopic expression genetics [Clusterin] Heat-Shock Response |
| Zdroj: | The journal of biological chemistry 287(52), 43765-43776 (2012). doi:10.1074/jbc.M112.389007 |
| DOI: | 10.1074/jbc.M112.389007 |
| Popis: | The heat shock response (HSR) is an evolutionarily conserved pathway designed to maintain proteostasis and to ameliorate toxic effects of aberrant protein folding. We have studied the modulation of the HSR by the scrapie prion protein (PrP(Sc)) and amyloid β peptide (Aβ) and investigated whether an activated HSR or the ectopic expression of individual chaperones can interfere with PrP(Sc)- or Aβ-induced toxicity. First, we observed different effects on the HSR under acute or chronic exposure of cells to PrP(Sc) or Aβ. In chronically exposed cells the threshold to mount a stress response was significantly increased, evidenced by a decreased expression of Hsp72 after stress, whereas an acute exposure lowered the threshold for stress-induced expression of Hsp72. Next, we employed models of PrP(Sc)- and Aβ-induced toxicity to demonstrate that the induction of the HSR ameliorates the toxic effects of both PrP(Sc) and Aβ. Similarly, the ectopic expression of cytosolic Hsp72 or the extracellular chaperone clusterin protected against PrP(Sc)- or Aβ-induced toxicity. However, toxic signaling induced by a pathogenic PrP mutant located at the plasma membrane was prevented by an activated HSR or Hsp72 but not by clusterin, indicating a distinct mode of action of this extracellular chaperone. Our study supports the notion that different pathological protein conformers mediate toxic effects via similar cellular pathways and emphasizes the possibility to exploit the heat shock response therapeutically. |
| Databáze: | OpenAIRE |
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