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Updated: Jun 13, 2026
08:41
Monitoring Endoplasmic Reticulum Calcium Homeostasis Using a Gaussia Luciferase SERCaMP
Published on: September 6, 2015
Endoplasmic reticulum Ca2+ increases enhance mutant glucocerebrosidase proteostasis
Derrick Sek Tong Ong1, Ting-Wei Mu, Amy E Palmer
1Department of Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA.
Nature Chemical Biology
|May 11, 2010
Summary
Increasing endoplasmic reticulum (ER) calcium enhances mutant enzyme homeostasis in Gaucher's disease. This improves enzyme folding and function by boosting chaperone activity, offering a potential therapeutic strategy.
Area of Science:
- Biochemistry
- Cell Biology
- Genetics
Background:
- Lysosomal storage diseases involve mutant enzyme dysfunction.
- Altering intracellular calcium partially restores enzyme homeostasis in some diseases.
- The precise mechanism linking calcium and enzyme restoration remains unclear.
Purpose of the Study:
- To investigate the hypothesis that increased endoplasmic reticulum (ER) calcium enhances mutant lysosomal enzyme folding, trafficking, and function.
- To elucidate the role of ER calcium in chaperone-mediated protein quality control.
Main Methods:
- Manipulating ER calcium levels via ryanodine receptor antagonists/RNAi or SERCA2b overexpression.
- Assessing mutant glucocerebrosidase (GC) homeostasis in Gaucher disease patient-derived cells.
- Analyzing the calnexin folding pathway and ER-associated degradation (ERAD).
Main Results:
- Increased ER calcium levels enhanced mutant GC homeostasis in Gaucher disease cells.
- Elevated ER calcium concentration improved the folding of misfolding-prone mutant enzymes.
- This led to increased lysosomal GC concentration and activity, with reduced ERAD.
Conclusions:
- Endoplasmic reticulum (ER) calcium levels play a crucial role in restoring mutant enzyme homeostasis.
- Enhanced ER calcium boosts chaperone function within the calnexin pathway, promoting proper folding and trafficking.
- This strategy offers a promising avenue for therapeutic intervention in Gaucher's disease and potentially other lysosomal storage disorders.
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