TY - JOUR
T1 - Oral curcumin mitigates the clinical and neuropathologic phenotype of the Trembler-J mouse
T2 - A potential therapy for inherited neuropathy
AU - Khajavi, Mehrdad
AU - Shiga, Kensuke
AU - Wiszniewski, Wojciech
AU - He, Feng
AU - Shaw, Chad A.
AU - Yan, Jiong
AU - Wensel, Theodore G.
AU - Snipes, G. Jackson
AU - Lupski, James R.
N1 - Funding Information:
We thank Dr. Dorothy Lewis and Cassandra Horne for their technical assistance at the flow-cytometry core facility at Baylor College of Medicine. We also thank Dr. Richard Paylor, for his assistance with the behavioral studies at the behavioral core; Zheng Wang, for mass spectrometry analysis; and Drs. K. Szigeti, K. Inoue, and K. Walz, for critical review of our manuscript. This study was supported in part by the National Institutes of Neurological Disorders and Stroke, National Institutes of Health, grant R01 NS27042 (to J.R.L.); the Muscular Dystrophy Association (to J.R.L. and G.J.S.), and the CMT Association (to J.R.L.)
PY - 2007/9
Y1 - 2007/9
N2 - Mutations in myelin genes cause inherited peripheral neuropathies that range in severity from adult-onset Charcot-Marie-Tooth disease type 1 to childhood-onset Dejerine-Sottas neuropathy and congenital hypomyelinating neuropathy. Many myelin gene mutants that cause severe disease, such as those in the myelin protein zero gene (MPZ) and the peripheral myelin protein 22 gene (PMP22), appear to make aberrant proteins that accumulate primarily within the endoplasmic reticulum (ER), resulting in Schwann cell death by apoptosis and, subsequently, peripheral neuropathy. We previously showed that curcumin supplementation could abrogate ER retention and aggregation-induced apoptosis associated with neuropathy-causing MPZ mutants. We now show reduced apoptosis after curcumin treatment of cells in tissue culture that express PMP22 mutants. Furthermore, we demonstrate that oral administration of curcumin partially mitigates the severe neuropathy phenotype of the Trembler-J mouse model in a dose-dependent manner. Administration of curcumin significantly decreases the percentage of apoptotic Schwann cells and results in increased number and size of myelinated axons in sciatic nerves, leading to improved motor performance. Our findings indicate that curcumin treatment is sufficient to relieve the toxic effect of mutant aggregation-induced apoptosis and improves the neuropathologic phenotype in an animal model of human neuropathy, suggesting a potential therapeutic role in selected forms of inherited peripheral neuropathies.
AB - Mutations in myelin genes cause inherited peripheral neuropathies that range in severity from adult-onset Charcot-Marie-Tooth disease type 1 to childhood-onset Dejerine-Sottas neuropathy and congenital hypomyelinating neuropathy. Many myelin gene mutants that cause severe disease, such as those in the myelin protein zero gene (MPZ) and the peripheral myelin protein 22 gene (PMP22), appear to make aberrant proteins that accumulate primarily within the endoplasmic reticulum (ER), resulting in Schwann cell death by apoptosis and, subsequently, peripheral neuropathy. We previously showed that curcumin supplementation could abrogate ER retention and aggregation-induced apoptosis associated with neuropathy-causing MPZ mutants. We now show reduced apoptosis after curcumin treatment of cells in tissue culture that express PMP22 mutants. Furthermore, we demonstrate that oral administration of curcumin partially mitigates the severe neuropathy phenotype of the Trembler-J mouse model in a dose-dependent manner. Administration of curcumin significantly decreases the percentage of apoptotic Schwann cells and results in increased number and size of myelinated axons in sciatic nerves, leading to improved motor performance. Our findings indicate that curcumin treatment is sufficient to relieve the toxic effect of mutant aggregation-induced apoptosis and improves the neuropathologic phenotype in an animal model of human neuropathy, suggesting a potential therapeutic role in selected forms of inherited peripheral neuropathies.
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U2 - 10.1086/519926
DO - 10.1086/519926
M3 - Article
C2 - 17701891
AN - SCOPUS:34548219064
SN - 0002-9297
VL - 81
SP - 438
EP - 453
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 3
ER -