Oral curcumin mitigates the clinical and neuropathologic phenotype of the Trembler-J mouse: A potential therapy for inherited neuropathy

Mehrdad Khajavi, Kensuke Shiga, Wojciech Wiszniewski, Feng He, Chad A. Shaw, Jiong Yan, Theodore G. Wensel, G. Jackson Snipes, James R. Lupski

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)438-453
Number of pages16
JournalAmerican Journal of Human Genetics
Volume81
Issue number3
DOIs
StatePublished - Sep 2007
Externally publishedYes

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Curcumin
Phenotype
Myelin P0 Protein
Apoptosis
Genes
Myelin Proteins
Schwann Cells
Myelin Sheath
Endoplasmic Reticulum
Therapeutics
Hereditary Sensory and Motor Neuropathy
Charcot-Marie-Tooth Disease
Poisons
Peripheral Nervous System Diseases
Sciatic Nerve
Oral Administration
Axons
Cell Death
Animal Models
Mutation

ASJC Scopus subject areas

  • Genetics

Cite this

Oral curcumin mitigates the clinical and neuropathologic phenotype of the Trembler-J mouse : A potential therapy for inherited neuropathy. / Khajavi, Mehrdad; Shiga, Kensuke; Wiszniewski, Wojciech; He, Feng; Shaw, Chad A.; Yan, Jiong; Wensel, Theodore G.; Snipes, G. Jackson; Lupski, James R.

In: American Journal of Human Genetics, Vol. 81, No. 3, 09.2007, p. 438-453.

Research output: Contribution to journalArticle

Khajavi, Mehrdad ; Shiga, Kensuke ; Wiszniewski, Wojciech ; He, Feng ; Shaw, Chad A. ; Yan, Jiong ; Wensel, Theodore G. ; Snipes, G. Jackson ; Lupski, James R. / Oral curcumin mitigates the clinical and neuropathologic phenotype of the Trembler-J mouse : A potential therapy for inherited neuropathy. In: American Journal of Human Genetics. 2007 ; Vol. 81, No. 3. pp. 438-453.
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