Oral Curcumin Mitigates the Clinical and Neuropathologic Phenotype of the Trembler-J Mouse: A Potential Therapy for Inherited Neuropathy

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.

PMP22 exon 4 deletion causes ER retention of PMP22 and a gain‐of‐function allele in CMT1E

“…Leu16Pro PMP22 has been shown to be retained in the ER of Schwann cells in Tr J mice 32. Moreover, the mice have demonstrated improvement following treatment with curcumin to reduce ER stress 32. Similar results have been found in two missense mutations in myelin protein zero (MPZ) that cause CMT1B.…”

“…Both Tr29 and Tr J 30, 31 mutations cause DSS in humans, and the mice can be used to model the human neuropathies. Leu16Pro PMP22 has been shown to be retained in the ER of Schwann cells in Tr J mice 32. Moreover, the mice have demonstrated improvement following treatment with curcumin to reduce ER stress 32.…”

Experimental Therapeutics in Hereditary Neuropathies: The Past, the Present, and the Future

“…24,32 Curcumin appears well tolerated in humans in doses as high as 12 g/day, and protects against apoptosis in cell cultures expressing MPZ or PMP22 mutations that ordinarily lead to intracellular aggregates and apoptosis. 24,32 Newborn Trembler-J mice with missense Pmp22 mutations that are associated with severe human CMT1 show marked improvement in their clinical and pathologic phenotype on curcumin therapy. 32 Studies in this model indicate that curcumin does not affect PMP22 levels, but rather likely alleviates mutant PMP22-induced SC apoptosis.…”

“…24,32 Newborn Trembler-J mice with missense Pmp22 mutations that are associated with severe human CMT1 show marked improvement in their clinical and pathologic phenotype on curcumin therapy. 32 Studies in this model indicate that curcumin does not affect PMP22 levels, but rather likely alleviates mutant PMP22-induced SC apoptosis. 32 Precisely how curcumin is active in these models is unclear; its effects may variously occur via release of mutant protein from the endoplasmic reticulum, by alleviating sequestration of endoplasmic reticulum chaperones, through reversal of the impairment in cellular protein synthesis and trafficking associated with an unregulated unfolded protein response, or by correction of misfolding of mutant proteins.…”

“…32 Precisely how curcumin is active in these models is unclear; its effects may variously occur via release of mutant protein from the endoplasmic reticulum, by alleviating sequestration of endoplasmic reticulum chaperones, through reversal of the impairment in cellular protein synthesis and trafficking associated with an unregulated unfolded protein response, or by correction of misfolding of mutant proteins. 24,32 Curcumin is thus a potential therapy for forms of CMT that are associated with endoplasmic reticulum aggregate formation and protein misfolding.…”