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Published on: April 24, 2021
Curcumin treatment abrogates endoplasmic reticulum retention and aggregation-induced apoptosis associated with
Mehrdad Khajavi1, Ken Inoue, Wojciech Wiszniewski
1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
Abstract:
Mutations in MPZ, the gene encoding myelin protein zero (MPZ), the major protein constituent of peripheral myelin, can cause the adult-onset, inherited neuropathy Charcot-Marie-Tooth disease, as well as the more severe, childhood-onset Dejerine-Sottas neuropathy and congenital hypomyelinating neuropathy. Most MPZ-truncating mutations associated with severe forms of peripheral neuropathy result in premature termination codons within the terminal or penultimate exons that are not subject to nonsense-mediated decay and are stably translated into mutant proteins with potential dominant-negative activity. However, some truncating mutations at the 3' end of MPZ escape the nonsense-mediated decay pathway and cause a mild peripheral neuropathy phenotype. We examined the functional properties of MPZ-truncating proteins that escaped nonsense-mediated decay, and we found that frameshift mutations associated with severe disease cause an intracellular accumulation of mutant proteins, primarily within the endoplasmic reticulum (ER), which induces apoptosis. Curcumin, a chemical compound derived from the curry spice tumeric, releases the ER-retained MPZ mutants into the cytoplasm accompanied by a lower number of apoptotic cells. Our findings suggest that curcumin treatment is sufficient to relieve the toxic effect of mutant aggregation-induced apoptosis and may potentially have a therapeutic role in treating selected forms of inherited peripheral neuropathies.
Insights
Curcumin may treat inherited neuropathies. This study shows curcumin relieves toxic MPZ mutant protein buildup in cells, reducing apoptosis and suggesting a therapeutic role for Charcot-Marie-Tooth disease.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Mutations in the myelin protein zero (MPZ) gene cause inherited peripheral neuropathies like Charcot-Marie-Tooth disease.
- Severe MPZ mutations often lead to truncated proteins that accumulate and cause disease.
- Some MPZ mutations escape cellular quality control (nonsense-mediated decay), leading to milder or severe phenotypes.
Purpose of the Study:
- To investigate the functional consequences of MPZ-truncating proteins that escape nonsense-mediated decay.
- To explore the therapeutic potential of curcumin in mitigating the toxic effects of these mutant proteins.
Main Methods:
- Analysis of MPZ-truncating mutations that escape nonsense-mediated decay.
- Cellular studies examining protein accumulation, endoplasmic reticulum (ER) stress, and apoptosis.
- Treatment of cells with curcumin to assess its effect on mutant protein aggregation and cell death.
Main Results:
- Frameshift MPZ mutations associated with severe neuropathy cause mutant proteins to accumulate in the ER, inducing apoptosis.
- Curcumin treatment reduced ER-retained MPZ mutants and decreased the number of apoptotic cells.
- Curcumin demonstrated the ability to alleviate toxic effects of mutant protein aggregation.
Conclusions:
- MPZ mutant proteins escaping nonsense-mediated decay can accumulate in the ER, leading to apoptosis and peripheral neuropathy.
- Curcumin shows therapeutic potential by reducing ER-stress and apoptosis caused by these mutant proteins.
- Curcumin may offer a treatment strategy for specific inherited peripheral neuropathies.