New insights into Wnt signaling alterations in amyotrophic lateral sclerosis: a potential therapeutic target?

Abstract

Amyotrophic lateral sclerosis is a fatal neurodegenerative disorder characterized by upper and lower motor neuron degeneration, which leads to progressive paralysis of skeletal muscles and, ultimately, respiratory failure between 2-5 years after symptom onset. Unfortunately, currently accepted treatments for amyotrophic lateral sclerosis are extremely scarce and only provide modest benefit. As a consequence, a great effort is being done by the scientific community in order to achieve a better understanding of the different molecular and cellular processes that influence the progression and/or outcome of this neuropathological condition and, therefore, unravel new potential targets for therapeutic intervention. Interestingly, a growing number of experimental evidences have recently shown that, besides its well-known physiological roles in the developing and adult central nervous system, the Wnt family of proteins is involved in different neuropathological conditions, including amyotrophic lateral sclerosis. These proteins are able to modulate, at least, three different signaling pathways, usually known as canonical (β-catenin dependent) and non-canonical (β-catenin independent) signaling pathways. In the present review, we aim to provide a general overview of the current knowledge that supports the relationship between the Wnt family of proteins and its associated signaling pathways and amyotrophic lateral sclerosis pathology, as well as their possible mechanisms of action. Altogether, the currently available knowledge suggests that Wnt signaling modulation might be a promising therapeutic approach to ameliorate the histopathological and functional deficits associated to amyotrophic lateral sclerosis , and thus improve the progression and outcome of this neuropathology.

Keywords: ALS; Frizzled; Wnt; astrocytes; human; microglia; motor neuron; neurodegeneration; neuroinflammation; spinal cord.

Figure 1

Schematic overview of Wnt signaling pathways. (A) In the canonical Wnt pathway, the absence of Wnt signal leads to proteasomal degradation of β‐catenin mediated by a multiprotein destruction complex including GSK-3β and CK1α kinases, responsible of β‐catenin phosphorylation. The binding of the Wnt ligand to its Fz receptor and to LRP5/6 co-receptor leads to the recruitment of DVL together with the destruction complex to the cell membrane. As a consequence, GSK-3β and CK1α mediated phosphorylation of β-catenin is inhibited, and the stabilized β-catenin is translocated to the nucleus where it serves as co-activator for Tcf/LEF transcription factors. (B) In the non-canonical Wnt/Ca²⁺ signaling pathway, the binding of Wnt ligands to their specific receptors activates PLC, leading to intracellular Ca²⁺ release and the subsequent activation of PKC and CaMKII which, in turn, regulate NF-AT transcription factor and gene expression. (C) In the non-canonical Wnt/PCP signaling pathway, the interaction of Wnt ligand with the receptor triggers a signaling cascade that involves small Rho-family GTPases and downstream effectors such as JNK and ROCK, which in turn modulate cytoskeleton organization and gene expression (modified from Gonzalez-Fernandez et al., 2016a). CaMKII: Calcium-calmodulin-dependent protein kinase II; CK1α: β‐catenin phosphorylation casein kinase 1; DVL: Dishevelled; Fz: Frizzled; GSK-3β: glycogen synthase kinase 3β; NF-AT: nuclear transcription factor of activated T-cells; PKC: protein kinase C; Tcf: T cell factor family.

Figure 2

Schematic representation of Wnt-related signaling dysregulations and their hypothetical involvement in ALS neuropathology. At pathological state, a general gene expression dysregulation of Wnt family members was described in both ALS transgenic mice and human spinal cord. The main current findings highlight the upregulation of several Wnt proteins by astrocytes (Wnt1, Wnt2, Wnt3a, Wnt4, Wnt5a, Wnt7a, Wif1, Fz1, Fz2, β-catenin and Cyclin D1) that may be involved in regulating astrocyte important processes such as proliferation and activation. Furthermore, at least Wnt5a seems to have a role in ALS neuroinflammation by modulating microglial activation and expansion. On the other hand, neurons seem to undergo downregulated in some Wnt family members (Wnt1, Wnt5a and Fz2) and Wnt/β-catenin signaling appear to decay, which might point out to an alteration of cell survival-related signaling pathways. However, other Wnt signaling components (Ryk, aPKC and Cyclin D1) related with axonal dysfunction and the balance between neuronal death and survival processes appear to be upregulated in ALS neurons, suggesting an attempt to promote their own survival and functioning. ALS: Amyotrophic lateral sclerosis. ↑: Upregulation/increase; ↓: downregulation/decrease; aPKC: atypical protein kinase C; ALS: amyotrophic lateral sclerosis; Fz: Frizzled; Ryk: receptor-like tyrosine kinase; Wif1: Wnt inhibitory factor 1.