title: Curcumin facilitates a transitory cellular stress response in Trembler-J mice.
abstract: We have previously shown that oral administration of curcumin significantly decreases the percentage of apoptotic Schwann cells and partially mitigates the severe neuropathy phenotype of the Trembler-J (Tr-J) mouse model in a dose-dependent manner. Here we compared the gene expression in sciatic nerves of 2-week-old pups and adult Tr-J with the same age groups of wild-type mice and found a significant increase in gene expression for hypoxia, inflammatory response and heat-shock proteins, the latter specifically the Hsp70 family, in Tr-J mice. We also detected an activation of different branches of unfolded protein responses (UPRs) in Tr-J mice. Administering curcumin results in lower expression of UPR markers suggesting it relieves endoplasmic reticulum (ER) cell stress sensors in sciatic nerves of Tr-J mice while the level of heat-shock proteins stays comparable to untreated Tr-J mice. We further tested if Hsp70 levels could influence the severity of the Tr-J neuropathy. Notably, reduced dosage of the Hsp70 strongly potentiates the severity of the Tr-J neuropathy, though the absence of Hsp70 had little effect in wild-type mice. In aggregate, these data provide further insights into the pathological disease mechanisms caused by myelin gene mutations and further support the exploration of curcumin as a therapeutic approach for selected forms of inherited neuropathy and potentially for other genetic diseases due to ER-retained mutants.
authors.affiliation: Department of Molecular and Human Genetics.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Davut
authors.initials: D
authors.lastname: Pehlivan
authors.forename: Wojciech
authors.initials: W
authors.lastname: Wiszniewski
authors.forename: Christine R
authors.initials: CR
authors.lastname: Beck
authors.forename: G Jackson
authors.initials: GJ
authors.lastname: Snipes
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Khajavi
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D003474:Curcumin / Q000494:pharmacology*; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009154:Mutation; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism; D010523:Peripheral Nervous System Diseases / Q000473:pathology*; D012584:Sciatic Nerve / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D056811:Unfolded Protein Response
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D018840:HSP70 Heat-Shock Proteins; D009185:Myelin Proteins; C489545:Pmp22 protein, mouse; D003474:Curcumin