Wnt and lithium: a common destiny in the therapy of nervous system pathologies?

Abstract

Wnt signaling is required for neurogenesis, the fate of neural progenitors, the formation of neuronal circuits during development, neuron positioning and polarization, axon and dendrite development and finally for synaptogenesis. This signaling pathway is also implicated in the generation and differentiation of glial cells. In this review, we describe the mechanisms of action of Wnt signaling pathways and their implication in the development and correct functioning of the nervous system. We also illustrate how a dysregulated Wnt pathway could lead to psychiatric, neurodegenerative and demyelinating pathologies. Lithium, used for the treatment of bipolar disease, inhibits GSK3β, a central enzyme of the Wnt/β-catenin pathway. Thus, lithium could, to some extent, mimic Wnt pathway. We highlight the possible dialogue between lithium therapy and modulation of Wnt pathway in the treatment of the diseases of the nervous system.

Downregulation of canonical Wnt signaling in hippocampus of SAMP8 mice

“…Consequently, tau phosphorylation increases, which results in its aggregation, destabilization of axonal microtubules, and neuronal loss. In this regard, modulation of Wnt by lithium, a well-known inhibitor of GSK-3 (Noble et al, 2005), sheds light on a promising therapeutic strategy for the treatment not only of AD but also for other neurodegenerative and psychiatric disorders (Meffre et al, 2014).…”

Regulation of seminiferous tubule-associated stem Leydig cells in adult rat testes

“…We also found that there is a robust stimulatory effect of lithium on stem cell differentiation. This metal is of particular interest because of its reported effects on the activation of Wnt signaling by inhibiting GSK3β (33). As yet, the molecular mechanism by which this factor acts remains uncertain.…”

Lithium chloride stimulates PLP and MBP expression in oligodendrocytes via Wnt/β-catenin and Akt/CREB pathways

“…After its translocation into the nucleus, b-catenin interacts with its nuclear partners (i.e. TCF/LEF transcription factors) to modulate gene expression (for review, Meffre et al, 2013).…”

“…They can be re-expressed after demyelinating episodes, where they contribute to remyelination. Demyelination occurs after injuries of the CNS such as traumatic brain injury or during acute episodes of neurodegeneration observed in demyelinating and neurodegenerative diseases (Meffre et al, 2013;El Waly et al, 2014). Remyelination process is achieved by oligodendrocytes newly generated following the recruitment and differentiation of Oligodendrocyte Precursor Cells (OPCs).…”