TY - JOUR
T1 - Curcumin treatment abrogates endoplasmic reticulum retention and aggregation-induced apoptosis associated with neuropathy-causing myelin protein zero-truncating mutants
AU - Khajavi, Mehrdad
AU - Inoue, Ken
AU - Wiszniewski, Wojciech
AU - Ohyama, Tomoko
AU - Snipes, G. Jackson
AU - Lupski, James R.
N1 - Funding Information:
We thank Dr. Bruce Trapp for providing P0 antibody. This study was supported in part by the Japanese Ministry of Health, Labor, and Welfare research grant 16B-1 for Nervous and Mental Disorders (to K.I.); by the Japanese Ministry of Education, Culture, Sports, Science and Technology grant-in-aid for scientific research 17390102 (to K.I.); by the U.S. National Institute for Neurological Disorders and Strokes, U.S. National Institutes of Health, grant R01 NS27042 (to J.R.L.); and by the Muscular Dystrophy Association (to J.R.L. and G.J.S.).
PY - 2005/11
Y1 - 2005/11
N2 - 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 Bejerine-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.
AB - 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 Bejerine-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.
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U2 - 10.1086/497541
DO - 10.1086/497541
M3 - Article
C2 - 16252242
AN - SCOPUS:27244435246
SN - 0002-9297
VL - 77
SP - 841
EP - 850
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 5
ER -