Cartoons in art class - Monty is getting ready for Easter break, but not in the Maldives
Today’s post may sound very complicated and narrow, but it is very relevant to people with the following: -
· Pitt Hopkins Syndrome (insufficient expression of the Transcription Factor #4 TCF4 gene)
· Multiple Sclerosis
· Some Mental Retardation/Intellectual Disability (MR/ID)
· Schizophrenia
· Impaired Wnt signalling
· Perhaps PAK1 inhibitor responders
I do feel that Multiple Sclerosis could be treated very much better if some effort was made to translate the existing science, freely available to all, into therapy. You could greatly improve many people’s lives just by repurposing cheap existing drugs.
In simple terms, to produce myelin that you need to coat axons in your brain, you need a type of cell called an oligodendrocyte (OL). You need a lot of these cells and you need them to get busy. They place tiny pieces of white insulation along axons of your brain cells, this produces the so called “white matter”. These pieces of insulation are needed to make electrical signals flow correctly in your brain.
It has been shown that in some people the oligodendrocyte precursors (OLPs) do not “mature” and instead get stuck as premyelinated oligodendrocytes (pre-OL). That means reduced myelination and loss of white matter.
It is clearly shown in the graphic below: -
Tcf4 is expressed in oligodendrocyte lineage in human developmental white matter and in active areas of MS lesions. (A) Tcf4 is expressed in white matter tracts during myelination of human developmental brain at postnatal age 1 mo, 3.5 mo, and 16 mo, but is not expressed by 7 yr. Tcf4 colocalizes with Olig2 when expressed in the developing human corpus callosum. (B) Tcf4 protein expression is evident in active MS lesions, but it is not seen in normal-appearing white matter (NAWM) or in the core of chronic MS lesions. An illustrative MS case is shown with several lesion types present. NAWM stains with Luxol Fast Blue (LFB) and contains sparse LN3(HLA-DR)-positive inflammatory cells, organized SMI-31 axon fibers, and no Tcf4-positive cells. Chronic plaques have sparse LFB staining and LN3-positive cells, intact axons, but no Tcf4-positive cells. In contrast, Tcf4-positive cells are present in active areas of plaques with abundant LN3-positive cells and intact demyelinated axons. Tcf4 expression in active lesions colocalizes (open arrowheads) with a subset of Olig2 cells.
Don’t worry if you don't follow everything. There is nothing wrong with your white matter.
We come back to Wnt signalling that we covered in depth in older posts. This is a complex signalling pathway implicated in autism, some cancers and other conditions. You can both increase and reduce Wnt signalling, which will affect the transcription of numerous genes.
TCF4 is the Pitt Hopkins gene. We have across this syndrome several times, while it is rare, a milder miss-expression of the gene is actually quite common. Reduced expression of TCF4 is a common feature of MR/ID very broadly. TCF4 has been found to be over-expressed in schizophrenia.
People with Multiple Sclerosis (MS) have been found to have oligodendrocytes “stuck” as non-myelinating (premyelinated oligodendrocytes, pre-OL). Inhibiting the Wnt pathway might play a role in treatment during periods of acute demyelination, when there is a lack of newly minted myelin-producing oligodendrocytes. The study below does refer to Wnt inhibitors in the pipeline as potential cancer therapies. It looks to me that safe Wnt inhibitors like the cheap drugs widely used to treat children with parasites (Mebendazole/ Niclosamide) could be repurposed to treat the acute phase of multiple sclerosis.
Mebendazole/ Niclosamide are safe and dirt cheap, whereas the (slightly) disease changing MS drugs currently cost $50,000+ a year.
TCF4 links everything together
Wnt signalling needs to be active to block premyelinated oligodendrocytes into transforming into oligodendrocytes (OL). So by inhibiting Wnt signalling you may remove one of the problems in MS; you probably only need to do this during relapses of MS.
There actually is a finally stage to getting the oligodendrocytes (OL) to myelinate many axons and not be lazy.
In the jargon “dysregulation of Wnt–β-catenin signaling in OLPs results in profound delay of both developmental myelination and remyelination”.
A miss-expression of TCF4 is clearly also going to affect myelination and its does in both Pitt Hopkins and MS.
One feature of Pitt Hopkins (caused by haploinsufficiency of the transcription factor 4) is indeed delayed myelination measured via MRI at the age of 1. By the age of 9 white matter (the myelin-coated part of your brain) appears normal. This fits with what I highlighted in red under figure 6 above.
Nothing is simple. Activating Wnt signalling is known to increase expression of TCF4.
The progressive loss of CNS myelin in patients with multiple sclerosis (MS) has been proposed to result from the combined effects of damage to oligodendrocytes and failure of remyelination. A common feature of demyelinated lesions is the presence of oligodendrocyte precursors (OLPs) blocked at a premyelinating stage. However, the mechanistic basis for inhibition of myelin repair is incompletely understood. To identify novel regulators of OLP differentiation, potentially dysregulated during repair, we performed a genome-wide screen of 1040 transcription factor-encoding genes expressed in remyelinating rodent lesions. We report that ∼50 transcription factor-encoding genes show dynamic expression during repair and that expression of the Wnt pathway mediator Tcf4 (aka Tcf7l2) within OLPs is specific to lesioned—but not normal—adult white matter. We report that β-catenin signaling is active during oligodendrocyte development and remyelination in vivo. Moreover, we observed similar regulation of Tcf4 in the developing human CNS and lesions of MS. Data mining revealed elevated levels of Wnt pathway mRNA transcripts and proteins within MS lesions, indicating activation of the pathway in this pathological context. We show that dysregulation of Wnt–β-catenin signaling in OLPs results in profound delay of both developmental myelination and remyelination, based on (1) conditional activation of β-catenin in the oligodendrocyte lineage in vivo and (2) findings from APCMin mice, which lack one functional copy of the endogenous Wnt pathway inhibitor APC. Together, our findings indicate that dysregulated Wnt–β-catenin signaling inhibits myelination/remyelination in the mammalian CNS. Evidence of Wnt pathway activity in human MS lesions suggests that its dysregulation might contribute to inefficient myelin repair in human neurological disorders
Potential Tcf4-catenin activities in oligodendrocyte development
The pattern of Tcf4 protein expression, from P1 to P30 and during remyelination after injury, defines the window of potential canonical Wnt pathway functions. Within this context, we observed that Tcf4 expression marked ∼15%–20% of OLPs at any given stage assessed. These findings were consistent with two possibilities. First, Tcf4 expression could demarcate a subset of OLPs. Second, it was possible that Tcf4 expression transiently marks all (or the vast majority) of OLPs during development. Our functional evidence strongly supports the latter conclusion, based on the fact that activity of activated β-catenin is Tcf-dependent (van de Wetering et al. 2002), coupled with the robust phenotype in DA-Cat and APCMin animals, in which we observe pervasive effects of Wnt pathway dysregulation on myelin production throughout the CNS. Interestingly, although Tcf4 proteins are coexpressed with nuclear Olig1 proteins, Tcf4 segregated from cells expressing Olig1 mRNA transcripts, consistent with the possibility that Tcf4 is expressed at a transition stage when nuclear Olig1 proteins become down-regulated during remyelination.
Previous work has suggested inhibitory functions of Tcf4 on myelin basic protein gene expression in vitro (He et al. 2007), and our studies indicate that Tcf4 interactions with β-catenin inhibit myelination in vivo. Additional studies are warranted to rule out possible β-catenin-independent roles for Tcf4 in oligodendrocyte development. Although Wnt pathway activation has conventionally been thought of as activating gene targets, recent work has identified novel Tcf–β-catenin DNA regulatory binding sites that repress targets (Blauwwkamp et al. 2008). In this regard, one intriguing candidate target is HYCCIN (DRCTNNB1A), a Wnt-repressed target (Kawasoe et al. 2000) with essential roles in human myelination (Zara et al. 2006), which is expressed in rodent oligodendrocytes and down-regulated in Olig2cre/DA-Cat mice (Supplemental Fig. 8). Further studies are needed to better understand Tcf4–catenin function and its direct gene targets during oligodendrocyte lineage progression.
Wnt pathway dysregulation in OLPs as a mechanism leading to chronic demyelination in human white matter diseases
Therapeutic opportunities might arise from an enhanced understanding of the process regulating normal kinetics of remyelination. How might the negative regulatory role of the canonical Wnt pathway help to explain the pathology of demyelinating disease? Delayed remyelination due to Wnt pathway dysregulation in OLPs could lead to chronic demyelination by OLPs then missing a “critical window” for differentiation (Miller and Mi 2007; Franklin and Ffrench-Constant 2008). This “dysregulation model” of remyelination failure requires the Wnt pathway to be active during acute demyelination, as suggested by data from our animal systems and human MS tissue.
Canonical WNT signaling has been implicated in a variety of human diseases (Nelson and Nusse 2004), and gain-of-function mutations in β-catenin are etiologic in several cancers including the majority of colon adenocarcinomas. Approaches for treating Wnt-dependent cancers by promoting differentiation (and hence cell cycle arrest or apoptosis) using pharmacological inhibitors of the pathway are under development (Barker and Clevers 2005). It is possible that such antagonists might play a role in the therapeutic enhancement of remyelination by normalizing the kinetics of myelin repair. If so, the animal models described here (e.g., APC+/−) should be useful in preclinical testing. However, it is important to note that while dysregulation of a pathway might delay remyelination, it is overly simplistic to expect that inhibition of the same pathway would accelerate repair in the complex milieu of an MS lesion in which several inhibitory pathways might be active, compounded by the presence of myelin debris (Kotter et al. 2006). Indeed, because of the need to synergize with other processes (e.g., those associated with inflammation), accelerated differentiation might negatively affect repair (Franklin and Ffrench-Constant 2008). Further work is needed to comprehensively understand interactions of regulatory networks required for optimal remyelination and how these may be dysregulated in human demyelinating diseases.
Neurologic and ocular phenotype in Pitt-Hopkins syndrome and a zebrafish model.
Abstract
In this study, we performed an in-depth analysis of the neurologic and ophthalmologic phenotype in a patient with Pitt-Hopkins syndrome (PTHS), a disorder characterized by severe mental and motor retardation, carrying a uniallelic TCF4 deletion, and studied a zebrafish model. The PTHS-patient was characterized by high-resolution magnetic resonance imaging (MRI) with diffusion tensor imaging to analyze the brain structurally, spectral-domain optical coherence tomography to visualize the retinal layers, and electroretinography to evaluate retinal function. A zebrafish model was generated by knockdown of tcf4-function by injection of morpholino antisense oligos into zebrafish embryos and the morphant phenotype was characterized for expression of neural differentiation genes neurog1, ascl1b, pax6a, zic1, atoh1a, atoh2b. Data from PTHS-patient and zebrafish morphants were compared. While a cerebral MRI-scan showed markedly delayed myelination and ventriculomegaly in the 1-year-old PTHS-patient, no structural cerebral anomalies including no white matter tract alterations were detected at 9 years of age. Structural ocular examinations showed highly myopic eyes and an increase in ocular length, while retinal layers were normal. Knockdown of tcf4-function in zebrafish embryos resulted in a developmental delay or defects in terminal differentiation of brain and eyes, small eyes with a relative increase in ocular length and an enlargement of the hindbrain ventricle. In summary, tcf4-knockdown in zebrafish embryos does not seem to affect early neural patterning and regionalization of the forebrain, but may be involved in later aspects of neurogenesis and differentiation. We provide evidence for a role of TCF4/E2-2 in ocular growth control in PTHS-patients and the zebrafish model.
Conclusion
If you have a myelinating disease, you might want to read up on TCF4 and Wnt signalling. Probably not what the Minions take to read on the beach in the Maldives.
We also should recall the importance of what I am calling the "what, when and where" in neurological disorders. This is important for late onset disorders like schizophrenia, since the symptoms often develops in late teenage years and so it is potentially preventable, if identified early enough.
Today we see that TCF4 is expressed in white matter only in early childhood. If you knew what changes take place in the brains of children who go on to develop schizophrenia, you might well be able to prevent its onset.
Preventing some autism is already possible, as has been shown in mouse models, but in humans it is more complicated because of the "when" and quite literally the "where". There will be a post showing how the brain overgrowth typical of autism can be prevented using bumetanide, before it occurs, at least in mice.
Conclusion
If you have a myelinating disease, you might want to read up on TCF4 and Wnt signalling. Probably not what the Minions take to read on the beach in the Maldives.
We also should recall the importance of what I am calling the "what, when and where" in neurological disorders. This is important for late onset disorders like schizophrenia, since the symptoms often develops in late teenage years and so it is potentially preventable, if identified early enough.
Today we see that TCF4 is expressed in white matter only in early childhood. If you knew what changes take place in the brains of children who go on to develop schizophrenia, you might well be able to prevent its onset.
Preventing some autism is already possible, as has been shown in mouse models, but in humans it is more complicated because of the "when" and quite literally the "where". There will be a post showing how the brain overgrowth typical of autism can be prevented using bumetanide, before it occurs, at least in mice.
