Kings College in London seem to be more effective in dentistry than autism; they have just published research showing how they effectively regrew a tooth to repair a cavity. That is rather clever.
Perhaps soon to be a thing of the past?
Using biodegradable collagen sponges to deliver the treatment, the team applied low doses of small molecule glycogen synthase kinase (GSK-3) inhibitors to the tooth. They found that the sponge degraded over time and that new dentine replaced it, leading to a complete, natural repair.
The full paper is here:-
All very well, but what has this got to do with Autism?
As regular readers will be aware, autism turns out to be multigenic (it involves lots of different genes) and no single gene seems to account for more than one or two percent of cases. A small number of any of hundreds of possible genes can be disturbed and then affect so-called signaling pathways that control our bodies. These pathways have evolved over millions of years and can seem quite unnecessarily complex. The pathways overlap with each other and at certain critical points it seems like different genetic dysfunctions can lead to the same dysfunctional point, or nexus.
We previously saw one such nexus, IPR3, suggested by Gargus:-
but another one may be the Synaptic Wnt/GSK3β signaling hub.
We came across Wnt signaling in earlier posts. Among other things, it relates to those RASopathies that often lead to cognitive dysfunction; but RAS dysfunction can also lead to common cancers, so called RAS-dependent cancers.
Wnt signaling is also involved in hair growth and hair greying, as one of our more adventurous readers experienced. So using a PAK1 inhibitor to modulate the Wnt pathway may make your hair go grey.
BCL-2 is another autism gene that affects hair growth/loss.
It has been suggested by some of the very clever researchers (Chauhan and Chauhan) that the BDNF-Akt-Bcl2 anti-apoptotic signaling pathway is compromised in the brain of autistic subjects.
So while the gene Bcl-2 might be the dysfunction in one per cent of people, in more cases it is the pathway along which Bcl-2 lies, that is the problem.
There is also so called cross-talk between pathways connecting Bcl-2 to RAS.
Then you will see that some drugs affect both Bcl-2 and RAS. So on the one hand things get much more complicated than just 20,000 different genes, but on the other hand the really good interventions will likely solve multiple dysfunctions. This is why we have talk about a nexus, or hub, where different dysfunctions lead to common points.
It makes sense to focus on identifying the limited number of these hubs, rather than getting lost in thousands of possibly dysfunctional genes.
It makes sense to focus on identifying the limited number of these hubs, rather than getting lost in thousands of possibly dysfunctional genes.
GSK-3 (Glycogen synthase kinase 3)
This area is very complex and really only a few people, mainly cancer researchers, and at least one dentist, understand it.
In essence, among other effects, GSK-3 inhibitors activate Wnt signaling.
Glycogen synthase kinase 3 is a serine/threonine protein kinase that mediates the addition of phosphate molecules onto serine and threonine amino acid residues. First discovered in 1980 as a regulatory kinase for its namesake, Glycogen synthase ]GSK-3 has since been identified as a kinase for over forty different proteins in a variety of different pathways. In mammals GSK-3 is encoded by two known genes, GSK-3 alpha (GSK3A) and GSK-3 beta (GSK3B). GSK-3 has recently been the subject of much research because it has been implicated in a number of diseases, including Type II diabetes (Diabetes mellitus type 2), Alzheimer's Disease, inflammation, cancer, and bipolar disorder.
Glycogen synthase kinase-3 (GSK3) may be the busiest kinase in most cells, with over 100 known substrates to deal with. How does GSK3 maintain control to selectively phosphorylate each substrate, and why was it evolutionarily favorable for GSK3 to assume such a large responsibility? GSK3 must be particularly adaptable for incorporating new substrates into its repertoire, and we discuss the distinct properties of GSK3 that may contribute to its capacity to fulfill its roles in multiple signaling pathways. The mechanisms regulating GSK3 (predominantly post-translational modifications, substrate priming, cellular trafficking, protein complexes) have been reviewed previously, so here we focus on newly identified complexities in these mechanisms, how each of these regulatory mechanism contributes to the ability of GSK3 to select which substrates to phosphorylate, and how these mechanisms may have contributed to its adaptability as new substrates evolved. The current understanding of the mechanisms regulating GSK3 is reviewed, as are emerging topics in the actions of GSK3, particularly its interactions with receptors and receptor-coupled signal transduction events, and differential actions and regulation of the two GSK3 isoforms, GSK3α and GSK3β. Another remarkable characteristic of GSK3 is its involvement in many prevalent disorders, including psychiatric and neurological diseases, inflammatory diseases, cancer, and others. We address the feasibility of targeting GSK3 therapeutically, and provide an update of its involvement in the etiology and treatment of several disorders.
GSK-3 and Autism
The good news is that the Alzheimer’s researchers have already developed a GSK-3 inhibitor, the current favourite is called Tideglusib. This is also the one the clever dentists at King’s College used.
Researchers in Santiago, Chile, have proposed the role of GSK-3 in the onset and development of ASDs through direct modulation of Wnt/β-catenin signaling.
Figure 1: Wnt/β-catenin signaling in ASDs. Wnt binding to FZD-LRP5/6 complex receptor at the membrane recruits the destruction complex and inhibits GSK3β activity thus stabilizing β-catenin in the cytoplasm and nucleus. Activation of the Wnt/β-catenin pathway facilitates synaptic plasticity through the activation of voltage gated ion channels that allows activation of CAMK and CREB mediated transcription. Mutations in TSC associated with ASD prevent β-catenin degradation which results in a gain of function of the Wnt pathway. In the presynaptic terminal cadherin mediated cell adhesion between synapses is weakened by phosphorylation of β-catenin and synaptic vesicle clustering is enhanced through DVL1. Clustering is also dependent on NLGN/NRXN cell adhesion complexes. Both lithium (LiCl) and VPA activate Wnt/β-catenin signaling through inhibition of GSK3β activity. Conversely, in the absence of a Wnt ligand, activated GSK3β targets β-catenin for proteosome-mediated degradation. Mutations associated with DISC1 fail to inhibit GSK3β and thus activate Wnt/β-catenin pathway. In the presynaptic side Wnt signaling buffering of synaptic vesicles is inhibited and adherens junctions mediated by cadherins are strengthened.
This becomes more interesting because a clinical trial has already been put in motion to trial Tideglusib in autism. I am not sure if the Canadian researchers are just trying an Alzheimer’s drug on the off-chance it might help autism, or whether they are really up to speed with their Wnt signaling pathway. I suspect the former, but it does not really matter.
This might be of interest to our reader Alli in Switzerland.
Conclusion
It pays to read the science reports that appear to have nothing to do with autism.