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Published on: February 17, 2016
Lethal adulthood myelin breakdown by oligodendrocyte-specific Ddx54 knockout
Hiroaki Oizumi1, Yuki Miyamoto2,3, Chika Seiwa4
1Tsumura Kampo Laboratories, Tsumura & Co, Ami, Ibaraki 300-1192, Japan.
Abstract:
Multiple sclerosis (MS) is a leading disease that causes disability in young adults. We have previously shown that a DEAD-box RNA helicase Ddx54 binds to mRNA and protein isoforms of myelin basic protein (MBP) and that Ddx54 siRNA blocking abrogates oligodendrocyte migration and myelination. Herein, we show that MBP-driven Ddx54 knockout mice (Ddx54 fl/fl;MBP-Cre), after the completion of normal postnatal myelination, gradually develop abnormalities in behavioral profiles and learning ability, inner myelin sheath breakdown, loss of myelinated axons, apoptosis of oligodendrocytes, astrocyte and microglia activation, and they die within 7 months but show minimal peripheral immune cell infiltration. Myelin in Ddx54;MBP-Cre is highly vulnerable to the neurotoxicant cuprizone and Ddx54 knockdown greatly impairs myelination in vitro. Ddx54 expression in oligodendrocyte-lineage cells decreased in corpus callosum of MS patients. Our results demonstrate that Ddx54 is indispensable for myelin homeostasis, and they provide a demyelinating disease model based on intrinsic disintegration of adult myelin.
Insights
The DEAD-box RNA helicase Ddx54 is crucial for maintaining myelin integrity in the central nervous system. Its absence leads to progressive demyelination and neurological deficits, offering a new model for studying myelin disorders.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Multiple sclerosis (MS) is a significant cause of disability in young adults, characterized by myelin damage.
- Previous research identified DEAD-box RNA helicase Ddx54's role in binding myelin basic protein (MBP) mRNA and protein isoforms.
- Ddx54 knockdown was previously shown to impair oligodendrocyte migration and myelination.
Purpose of the Study:
- To investigate the in vivo function of Ddx54 in adult myelin maintenance.
- To establish a novel animal model for studying intrinsic myelin disintegration and demyelinating diseases.
Main Methods:
- Generation and analysis of MBP-driven Ddx54 knockout mice (Ddx54 fl/fl;MBP-Cre).
- Assessment of behavioral profiles, learning ability, and histological examination of the central nervous system.
- Evaluation of myelin vulnerability using the neurotoxicant cuprizone and in vitro Ddx54 knockdown experiments.
Main Results:
- Ddx54 knockout mice exhibit progressive behavioral and learning deficits, inner myelin sheath breakdown, axon loss, and oligodendrocyte apoptosis.
- These mice show increased susceptibility to cuprizone-induced demyelination and reduced myelination upon Ddx54 knockdown in vitro.
- Reduced Ddx54 expression was observed in oligodendrocyte-lineage cells in the corpus callosum of MS patients.
Conclusions:
- Ddx54 is essential for maintaining myelin homeostasis in the adult central nervous system.
- The Ddx54 knockout mouse model recapitulates key features of intrinsic myelin disintegration.
- These findings highlight Ddx54 as a potential therapeutic target for demyelinating diseases like MS.
