Mutant glucocerebrosidase in Gaucher disease recruits Hsp27 to the Hsp90 chaperone complex for proteasomal degradation
Abstract
Gaucher disease (GD) is an inherited metabolic storage disorder characterized by mutations in the gene GBA1 encoding for glucocerebrosidase (GCase). These mutations result in protein misfolding and subsequent premature degradation. Recognition by the heat shock protein (hsp) 90 complex is crucial for targeting of mutant GCase to the proteasome, but the mechanisms governing this association are unclear. This study describes a novel recruitment of Hsp27 to the Hsp90 complex that is specific to misfolded mutant GCase. Both gene knockdown and pharmacologic inhibition of Hsp27 increased GCase levels in patient-derived fibroblasts. Reduction of Hsp27 may circumvent premature protein degradation and represents a viable potential therapeutic strategy in the treatment of protein misfolding disorders.
- Publication:
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Proceedings of the National Academy of Science
- Pub Date:
- January 2015
- DOI:
- 10.1073/pnas.1424288112
- Bibcode:
- 2015PNAS..112.1137Y