title: Curcumin treatment abrogates endoplasmic reticulum retention and aggregation-induced apoptosis associated with neuropathy-causing myelin protein zero-truncating mutants.
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.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Khajavi
authors.forename: Ken
authors.initials: K
authors.lastname: Inoue
authors.forename: Wojciech
authors.initials: W
authors.lastname: Wiszniewski
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ohyama
authors.forename: G Jackson
authors.initials: GJ
authors.lastname: Snipes
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
mesh_terms: D017209:Apoptosis; D003474:Curcumin / Q000627:therapeutic use*; D003711:Demyelinating Diseases / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology*; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D006367:HeLa Cells; D015417:Hereditary Sensory and Motor Neuropathy / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D009154:Mutation; D018993:Myelin P0 Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D018993:Myelin P0 Protein; D003474:Curcumin