GSK3β genetic variability in patients with Multiple Sclerosis.
ABSTRACT Glycogen synthase kinase-3 beta (GSK3β) is a ubiquitous kinase that is part of multiple signaling pathways. It has neurotrophic/neuroprotective effects by mediating the actions of neurotrophic molecules in the brain, thus providing neuroprotection through modulation of energy metabolism. Notably, it has been demonstrated that GSK3β is involved in Wnt-beta-catenin signaling, which contributes to the inhibition of myelination and remyelination processes in mammals. Three-hundred nineteen patients with MS and 294 age-matched controls were genotyped by allelic discrimination for four common GSK3β variants (rs2199503, rs9826659, rs334558 and rs6438552) tagging about 100% of GSK-3β variability. A statistically significant increased frequency of the rs334558 GG genotype was observed in patients as compared with controls (25.4% versus 17.7%, P=0.02; OR:1.58, 95%CI: 1.07-2.34). Stratifying MS patients according to the disease subtype, a statistically significant difference of rs334558 GG frequency was found between Relapsing Remitting (RR), but not Primary Progressive or Secondary MS, and controls (27.0% versus 17.7%, P=0.01; OR: 1.72, 95%CI: 1.13-2.61). GSK3β rs334558 is a susceptibility factor for MS. As it is located in the promoter region, a possible explanatory mechanism could be an influence of the variant on the gene transcription rate.
SourceAvailable from: Zezhi Li[Show abstract] [Hide abstract]
ABSTRACT: Myelination is critical to normal functioning of the vertebrate nervous system. In demyelinating diseases such as multiple sclerosis, oligodendrocytes, the myelinating cells in the central nervous system, are targeted, resulting in myelin loss, axonal damage, and severe functional impairment. While spontaneous remyelination has been proven a failure in multiple sclerosis, understanding the molecular mechanism underlying oligodendrocyte biology, myelination, and remyelination becomes crucial. To date, a series of signaling pathways in regulating oligodendrocyte development and remyelination have been suggested and, among them, the Wnt/β-catenin/Tcf pathway has been considered a negative factor in the myelinating process. However, this notion has been challenged by recent studies, which showed a pro-myelinating effect of this pathway. This review summarizes the current contradictory concepts concerning the role of the Wnt pathway in the oligodendrocyte development and remyelination process, attempts to address the potential mechanism underlying this controversy, and recommends caution in targeting the Wnt pathway as a potential demyelinating therapy.Molecular Neurobiology 11/2013; DOI:10.1007/s12035-013-8584-6 · 5.29 Impact Factor
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ABSTRACT: Failure of remyelination in diseases, such as multiple sclerosis (MS), leads to permanent axonal damage and irreversible functional loss. The mechanisms controlling remyelination are currently poorly understood. Recent studies implicate the cyclin-dependent kinase 5 (Cdk5) in regulating oligodendrocyte (OL) development and myelination in CNS. In this study, we show that Cdk5 is also an important regulator of remyelination. Pharmacological inhibition of Cdk5 inhibits repair of lysolecithin lesions. This inhibition is a consequence of Cdk5 disruption in neural cells because remyelination in slice cultures is blocked by Cdk5 inhibitors, whereas specific deletion of Cdk5 in OLs inhibits myelin repair. In CNP-Cre;Cdk5(fl/fl) conditional knock-out mouse (Cdk5 cKO), myelin repair was delayed significantly in response to focal demyelinating lesions compared with wild-type animals. The lack of myelin repair was reflected in decreased expression of MBP and proteolipid protein and a reduction in the total number of myelinated axons in the lesion. The number of CC1(+) cells in the lesion sites was significantly reduced in Cdk5 cKO compared with wild-type animals although the total number of oligodendrocyte lineage cells (Olig2(+) cells) was increased, suggesting that Cdk5 loss perturbs the transition of early OL lineage cell into mature OL and subsequent remyelination. The failure of remyelination in Cdk5 cKO animals was associated with a reduction in signaling through the Akt pathway and an enhancement of Gsk-3β signaling pathways. Together, these data suggest that Cdk5 is critical in regulating the transition of adult oligodendrocyte precursor cells to mature OLs that is essential for myelin repair in adult CNS.The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 07/2014; 34(31):10415-10429. DOI:10.1523/JNEUROSCI.0710-14.2014 · 6.75 Impact Factor
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ABSTRACT: Deciphering the molecular pathways involved in myelin gene expression is a major point of interest to better understand re/myelination processes. In this study, we investigated the role of Lithium Chloride (LiCl), a drug largely used for the treatment of neurological disorders, on the two major central myelin gene expression (PLP and MBP) in mouse oligodendrocytes. We show that LiCl enhances the expression of both PLP and MBP, by increasing mRNA amount and promoter activities. We investigated whether Wnt/β-catenin and/or Akt/CREB pathways are modulated by LiCl to regulate myelin gene expression. We showed that β -catenin is required both for PLP and MBP basal promoter activities and for LiCl-induced myelin gene stimulation. Furthermore, while CREB functionality does not influence PLP expression, MBP promoter activity depends on Akt/CREB activation. Finally, we show that LiCl can stimulate oligodendrocyte morphological maturation, and promote remyelination after lysolecithin-induced demyelination of organotypic cerebellar slice cultures. Our data provide mechanistic evidences that Akt/CREB together with β-catenin participate in the transcriptional control of PLP and MBP exerted by LiCl. Therefore, the use of LiCl to balance between β-catenin and CREB effectors could be considered as an efficient remyelinating strategy. Copyright © 2014. Published by Elsevier Ltd.Neuroscience 11/2014; 284C:962-971. DOI:10.1016/j.neuroscience.2014.10.064 · 3.33 Impact Factor