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Effect of curcumin in a mouse model of Pelizaeus-Merzbacher disease
Li-Hua Yu1, Toshifumi Morimura, Yurika Numata
1Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Japan.
Abstract:
PLP1 amino acid substitutions cause accumulation of misfolded protein and induce endoplasmic reticulum (ER) stress, causing Pelizaeus-Merzbacher disease (PMD), a hypomyelinating disorder of the central nerve system. Currently no effective therapy is available for PMD. Promoted by its curative effects in other genetic disease models caused by similar molecular mechanisms, we tested if curcumin, a dietary compound, can rescue the lethal phenotype of a PMD mouse model (myelin synthesis deficient, msd). Curcumin was administered orally to myelin synthesis deficit (msd) mice at 180 mg·kg(-1)·day(-1) from the postnatal day 3. We evaluated general and motor status, changes in myelination and apoptosis of oligodendrocytes by neuropathological and biochemical examination, and transcription levels for ER-related molecules. We also examined the pharmacological effect of curcumin in cell culture system. Oral curcumin treatment resulted in 25% longer survival (p<0.01). In addition, oligodendrocytes undergoing apoptosis were reduced in number (p<0.05). However, no apparent improvement in motor function, neurological phenotype, and myelin formation was observed. Curcumin treatment did not change the expression of ER stress markers and subcellular localization of the mutant protein in vitro and/or in vivo. Curcumin partially mitigated the clinical and pathological phenotype of msd mice, although molecular mechanisms underlying this curative effect are yet undetermined. Nonetheless, curcumin may serve as a potential therapeutic compound for PMD caused by PLP1 point mutations.
Insights
Curcumin extended survival and reduced oligodendrocyte apoptosis in a Pelizaeus-Merzbacher disease (PMD) mouse model. However, it did not improve motor function or myelination, suggesting a partially effective therapeutic role.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Pelizaeus-Merzbacher disease (PMD) is a fatal hypomyelinating disorder caused by PLP1 gene mutations.
- Misfolded PLP1 protein accumulation induces endoplasmic reticulum (ER) stress, contributing to oligodendrocyte death.
- Current therapeutic options for PMD are limited.
Purpose of the Study:
- To investigate the therapeutic potential of curcumin, a dietary compound, in a mouse model of PMD.
- To evaluate curcumin's effects on survival, neurological phenotype, myelination, and ER stress markers in the myelin synthesis deficient (msd) mouse model.
Main Methods:
- Oral administration of curcumin (180 mg·kg(-1)·day(-1)) to msd mice from postnatal day 3.
- Assessment of general and motor status, neuropathological changes, oligodendrocyte apoptosis, and ER-related gene expression.
- In vitro and in vivo examination of curcumin's pharmacological effects on mutant protein localization and ER stress.
Main Results:
- Curcumin treatment significantly increased survival by 25% (p<0.01) and reduced oligodendrocyte apoptosis (p<0.05).
- No significant improvement was observed in motor function, neurological phenotype, or myelin formation.
- Curcumin did not alter ER stress marker expression or mutant protein localization.
Conclusions:
- Curcumin partially mitigates the clinical and pathological phenotype of the msd mouse model.
- The precise molecular mechanisms underlying curcumin's beneficial effects remain to be determined.
- Curcumin shows promise as a potential therapeutic agent for PMD caused by PLP1 point mutations.