Curcumin Treatment Abrogates Endoplasmic Reticulum Retention and Aggregation-Induced Apoptosis Associated with Neuropathy-Causing Myelin Protein Zero–Truncating Mutants

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 12/2005; 77(5):841-50. DOI: 10.1086/497541
Source: PubMed


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.

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    • "Although the proband's father harboring the same mutation was asymptomatic, the finding implicates a variable modifier, and strong candidates include factors related to the ER stress response. The association of apoptosis with certain neurological disorders was reported recently (Inoue et al., 2004; Khajavi et al., 2005 "
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    ABSTRACT: Mutations in GABRG2, which encodes the γ2 subunit of GABAA receptors, can cause both genetic epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome. Most GABRG2 truncating mutations associated with Dravet syndrome result in premature termination codons (PTCs) and are stably translated into mutant proteins with potential dominant-negative effects. This study involved search for mutations in candidate genes for Dravet syndrome, namely SCN1A, 2A, 1B, 2B, GABRA1, B2, and G2. A heterozygous nonsense mutation (c.118C>T, p.Q40X) in GABRG2 was identified in dizygotic twin girls with Dravet syndrome and their apparently healthy father. Electrophysiological studies with the reconstituted GABAA receptors in HEK cells showed reduced GABA-induced currents when mutated γ2 DNA was cotransfected with wild-type α1 and β2 subunits. In this case, immunohistochemistry using antibodies to the α1 and γ2 subunits of GABAA receptor showed granular staining in the soma. In addition, microinjection of mutated γ2 subunit cDNA into HEK cells severely inhibited intracellular trafficking of GABAA receptor subunits α1 and β2, and retention of these proteins in the endoplasmic reticulum. The mutated γ2 subunit-expressing neurons also showed impaired axonal transport of the α1 and β2 subunits. Our findings suggested that different phenotypes of epilepsy, e.g., GEFS+ and Dravet syndrome (which share similar abnormalities in causative genes) are likely due to impaired axonal transport associated with the dominant-negative effects of GABRG2.
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    • "Curcumin, a molecule derived from the curry spice turmeric, has been demonstrated to stimulate the translocation of misfolded proteins from the endoplasmic reticulum to the plasma membrane, thereby reducing cytotoxicity of the mutant proteins [156] [157]. Khajavi et al. hypothesized that curcumin could have a protective effect on CMT1A and CMT1B forms, in which various myelin protein zero and PMP22 mutations cause intracellular accumulation of mutant proteins, primarily within the endoplasmic reticulum [156]. Previous report demonstrated that curcumin selectively activates human TRPA1 channels (Table 1) heterologously expressed in HEK293 cells and in native TRPA1-containing cells. "
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    • "Curcumin, the active component of the curry spice, turmeric, has been proposed to attenuate endoplasmic reticulum stress by a number of possible mechanisms. Previous examples of curcumin's potential therapeutic benefit include correcting the endoplasmic reticulum retention of the cystic fibrosis-related CFTR ÁF508 ion channel (Egan et al., 2004), truncated constructs of MPZ (Khajavi et al., 2005) and PMP22-containing CMT1E-associated point mutations (Khajavi et al., 2007). Furthermore, motor deficits in Trembler-J mice (harbouring CMT1E-associated point mutations in PMP22) improved when these mice were fed curcumin. "

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