Autophagy, Mitophagy, Calpains and mTOR in Autism, but also in aging, cancer, diabetes, Alzheimer's, Parkinson's, and Huntington's etc.

 Source:  http://www.tanpaku.org/autophagy/

I am writing a science heavy post all about a protein called mTOR.  It is one of those "cancer proteins" that are now heavily researched, very complicated, but clearly very connected to autism.

In today’s lead-in post, that was not supposed to get complicated, I will introduce new terms, Autophagy, Mitophagy and Calpains. 

There are some very interesting implications from the research, not least that you can reduce mTOR levels just by eating (a lot) less.  Indeed, this “starvation” diet has now been shown by the University of Newcastle to be able to reverse the onset of type 2 diabetes.  It also may suggest another reason for those Somali Autism clusters in the US and Sweden, where refugees from Somalia have been settled.  Just as a starvation diet reduces mTOR, excessive eating increases mTOR.  Via several mechanisms we will see that autism associates with high levels of mTOR.  While the hygiene hypotheses can be used to explain these autism “hotspots” among Somali refugees, a completely different reason might be the switch from relative starvation to an overabundant diet; this would trigger an increase in mTOR and therefore the increase in autism (and later diabetes and cancer in the wider group).

In today’s post we will find out about Autophagy/Mitophagy and see how they are relevant to autism.

We will see how they are generally controlled by mTOR.  PINK1, which we encountered in a previous post will reappear, as will Verapamil, that L-type calcium channel blocker that seems to affect so many things.

Not only does verapamil appear protective towards developing type 2 diabetes, but also now Huntingdon’s Disease.

Autophagy

Autophagy is a very complex process.

Here is a relatively plain English explanation:

The word autophagy is derived from Greek words “auto” meaning self and “phagy” meaning eating. Autophagy is a normal physiological process in the body that deals with destruction of cells in the body.

It maintains homeostasis or normal functioning by protein degradation and turnover of the destroyed cell organelles for new cell formation.

During cellular stress the process of Autophagy is upscaled and increased. Cellular stress is caused when there is deprivation of nutrients and/or growth factors.

Thus Autophagy may provide an alternate source of intracellular building blocks and substrates that may generate energy to enable continuous cell survival.

Autophagy and cell death

Autophagy also kills the cells under certain conditions. These are form of programmed cell death (PCD) and are called autophagic cell death. Programmed cell death is commonly termed apoptosis.

Autophagy is termed a nonapoptotic programmed cell death with different pathways and mediators from apoptosis.

Autophagy mainly maintains a balance between manufacture of cellular components and break down of damaged or unnecessary organelles and other cellular constituents.

There are some major degradative pathways that include proteasome that involves breaking down of most short-lived proteins.

Autophagy and stress

Autophagy enables cells to survive stress from the external environment like nutrient deprivation and also allows them to withstand internal stresses like accumulation of damaged organelles and pathogen or infective organism invasion.

Autophagy is seen in all eukaryotic systems including fungi, plants, slime mold, nematodes, fruit flies and insects, rodents (laboratory mice and rats), humans.

Types of autophagy

There are several types of Autophagy. These are:-

·         microautophagy – in this process the cytosolic components are directly taken up by the lysosome itself through the lysosomal membrane.

·         macroautophagy – this involves delivery of cytoplasmic cargo to the lysosome through the intermediary of a double membrane-bound vesicle. This is called an autophagosome that fuses with the lysosome to form an autolysosome.

·         Chaperone-mediated autophagy – in this process the targeted proteins are translocated across the lysosomal membrane in a complex with chaperone proteins (such as Hsc-70).  

·         micro- and macropexophagy

·         piecemeal microautophagy of the nucleus

·         cytoplasm-to-vacuole targeting (Cvt) pathway

Autophagy & Autism

Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits

Developmental alterations of excitatory synapses are implicated in autism spectrum disorders (ASDs). Here, we report increased dendritic spine density with reduced developmental spine pruning in layer V pyramidal neurons in postmortem ASD temporal lobe. These spine deficits correlate with hyperactivated mTOR and impaired autophagy. In Tsc2 ± ASD mice where mTOR is constitutively overactive, we observed postnatal spine pruning defects, blockade of autophagy, and ASD-like social behaviors. The mTOR inhibitor rapamycin corrected ASD-like behaviors and spine pruning defects in Tsc2 ± mice, but not in Atg7(CKO) neuronal autophagy-deficient mice or Tsc2 ± :Atg7(CKO) double mutants. Neuronal autophagy furthermore enabled spine elimination with no effects on spine formation. Our findings suggest that mTOR-regulated autophagy is required for developmental spine pruning, and activation of neuronal autophagy corrects synaptic pathology and social behavior deficits in ASD models with hyperactivated mTOR.

Verapamil, Autophagy and Calpains

Here we need to introduce another new term, the calpain.

Hyper activation of calpains is a feature of Alzheimer’s and Huntingdon’s disease.  This does lead to altered calcium homeostasis.

Nobody has really studied calpains and autism.  There is research into calpains and TBI (traumatic brain injury).

Since we know there is aberrant calcium channel activity in autism and even excessive physical calcium present in autistic brains, it seems possible that hyper activation of calpains may be occurring in autism.

We also know that calpains play a role in degrading PTEN, which then affects BDNF, in turn affecting mTOR activation.  So everything is highly interrelated.

Calpain may be released in the brain for up to a month after a head injury, and may be responsible for a shrinkage of the brain sometimes found after such injuries.

However, calpain may also be involved in a "resculpting" process that helps repair damage after injury.

Moreover, the hyperactivation of calpains is implicated in a number of pathologies associated with altered calcium homeostasis such as Alzheimer's disease

  

Calpain-2-mediated PTEN degradation contributes to BDNF-induced stimulation of dendritic protein synthesis

From: Biomarkers of Brain Injury

 Source:-  Stanford Huntingdon Disease (HD) Project

So if it was the case that in autism, as in HD, that there is excessive calpain activity, then it would be possible to increase autophagy simply by reducing the flow of calcium into the cells. 

So this might be yet another reason why Verapamil may be a good therapeutic choice for some people with autism.

Mitophagy & PINK1

Mitophagy is a necessary ongoing “spring cleaning” of damaged bits of mitochondria.

It appears that in some autism, this process goes awry and damaged mitochondria accumulate.

We saw in early posts that in brain samples from younger people with autism, abnormal mitochondria are typically found.

Mitochondrial abnormalities in temporal lobe of autistic brain

Children with autism have mitochondrial dysfunction, study finds

I should point out that there are various types of mitochondrial disease and dysfunction.

It appears that some people’s autism is solely the result of mitochondrial disease, but a much broader group have some mitochondrial dysfunction.

Mitophagy is the selective degradation of mitochondria by autophagy. It often occurs to defective mitochondria following damage or stress. This process was first mentioned by J.J. Lemasters in 2005, although lysosomes in the liver that contained mitochondrial fragments had been seen as early as 1962, “As part of almost every lysosome in these glucagon-treated cells it is possible to recognize a mitochondrion or a remnant of one. It was also mentioned in 1977 by scientists studying metamorphosis in silkworms, “...mitochondria develop functional alterations which would activate autophagy."  Mitophagy is key in keeping the cell healthy. It promotes turnover of mitochondria and prevents accumulation of dysfunctional mitochondria which can lead to cellular degeneration. It is mediated by Atg32 (in yeast) and NIP3-like protein X (NIX). Mitophagy is regulated by PINK1 and parkin protein. The occurrence of mitophagy is not limited to the damaged mitochondria but also involves undamaged ones.

Autophagy and mitophagy in cellular damage control

Mitochondrial dysfunction due to aberrant mTOR-regulated mitophagy in autism

This Mentored Research Scientist Development Award (K01) is designed to characterize the molecular mechanism underlying mitochondrial dysfunction in autism, with the eventual goal of identifying therapeutic interventions for mitochondrial defects. The applicant (Dr. Guomei Tang) is an Associate Research Scientist at Columbia University Medical Center (CUMC), where internationally renowned basic neuroscience research in psychiatry has been ongoing for many years. CUMC provides a rich environment that supports and encourages Dr. Tang's development and this K01 award will be instrumental for her successful transition to an independent research investigator. Dr. Tang has recruited an outstanding team of mentors, co-mentors, consultants and collaborators with extensive experience in mitochondrial biology and diseases, neuropathology, psychiatry neuropathology, neuroscience, molecular and cell biology, and mTOR-autophagy signaling. These experts will provide her with critical guidance and advice, and enhance her technical and scientific skills for the proposed research. The career development activities include tutorials, directed readings, course work, workshops for mitochondrial biology, skills in collaborating with clinicians and senior scientists, grant writing and presentations, and responsible conduct of research. Dr. Tang's long term research goal is to elucidate the molecular and cellular mechanisms underlying synaptic pathology in autism, and to provide insights into the pathogenesis and potential treatment for autism. To accomplish this, Dr. Tang will use a multidisciplinary approach combining biochemical, histological and imaging techniques to examine mitochondrial autophagy in postmortem autistic brain and mouse models. Her preliminary evidence indicates an association between mitochondrial defects and a dysregulation of mTOR-autophagy signaling in autistic brain. In mouse embryonic fibroblasts (MEFs) and neuronal cultures, mTOR hyperactivation inhibits autophagy, decreases mitochondrial membrane potential and causes an accumulation of damaged mitochondria. These results suggest that mitochondrial dysfunction in autism may result from aberrant mTOR- mediated mitophagy signaling. To address this hypothesis, Dr. Tang proposes 3 specific aims: 1) To determine whether mTOR hyper regulation inhibits neuronal mitophagy and causes mitochondrial dysfunction in ASD mouse models;2) To examine whether enhancing mitophagy rescues mitochondrial dysfunction in ASD mouse models; and 3) To confirm mitophagy defects in ASD postmortem brain and lymphoblasts. These data will be important for understanding the mechanism by which mTOR kinase regulates mitophagy, elucidating the mitochondrial pathophysiology that underlies ASD pathogenesis, and ultimately to design interventions effective in treatment. The knowledge and experience gained from this proposal will lead directly to a study of the effects of mitophagy defects and mitochondria dysfunction on synaptic pathology in autism, which will be proposed in an R01 grant application in 3-4 years of the award

Obesity & Autism

Briefly to return to obesity, since I just saw something interesting…

Since we know that over eating with increase mTOR and that hyper-activated mTOR in associated with several dysfunctions in autism, being obese and autistic is not a good idea.

In the US, where potent “psychiatric” drugs are widely prescribed for autism, almost a third of all adolescents with autism are obese, not just over-weight.  Weight gain is a known side effect of some of these drugs.

CDC Study Flags High Rate of Obesity among Teens with Autism

Conclusion

It would appear that hyperactivated mTOR in autism causes dysfunctions in autophagy/mitophagy.  This causes at least two subsequent dysfunctions:-

 ·        Synaptic pruning dysfunction.  There is a post all about this subject.

 Dendritic Spines in Autism – Why, and potentially how, to modify them

 ·        Mitochondrial dysfunction
 

If hyper activation of calpains is occurring in autism, this would explain some of the odd behaviour of Ca²⁺.  It would also again suggest Verapamil for a broader group of autism.

The numerous other connections between mTOR and autism, will be covered in upcoming post on mTOR, which will even include food intolerance. 

Tuning Wnt Signaling for more/fewer hairs and to optimize Dendritic Spine Morphology in Autism

Today’s post is about another example of how evolution can play jokes on us.  It really is the case that a signaling pathway that controls hair growth is the same that determines the number and shape of dendritic spines in the brain.

This is good news not just for Homer Simpson but for people interesting in perking up behavior and cognitive function in autism.

The post also connects several subjects that we have previously encountered - dendritic spines which are abnormal in autism, Wnt signaling which is implicated in cancer (and autism), statins, Ivermectin, CAPE found in some propolis and verapamil.  There is plenty of research to back all these connections, but strangely nobody seems to be applying them to develop any practical therapies.

I introduced dendritic spines in an earlier post.  Each neuron in your brain has hundreds of protruding spines.

Dendritic Spines in Autism – Why, and potentially how, to modify them

In that post I reported that PAK1, the gene NrCAM and the protein MTOR were all implicated in the dysfunction in both shape and number of these spines.

It now seems that there may be one even more critical pathway involved – Wnt. There are links between Wnt and PAK1, that appeared in several earlier posts.

You may recall that dendritic spines are constantly changing shape.  Their shape affects their function.  In many disorders, both the number and shape of the spines is dysfunctional.  It appears that the morphology (shape) can be modified, which implies you could affect behavior, memory, and cognitive function.

My follow up post of dendritic spines has yet to materialize, but here is a sneak preview, showing the progression of autism, schizophrenia and Alzheimer’s in terms of the number of dendritic spines.

Dendritic Spines and Wnt Signaling

Dendritic spines are constantly changing their shape and certain psychiatric disorders are characterized by different morphologies (shapes) of these spines.  It is not just the number of spines, but their shape which affects cognitive function, memory and behavior.

The Wnt signaling pathway also lies behind hair growth.

What is more, we know that Wnt signaling is dysfunctional in autism and we even now which the genes are that likely trigger of this dysfunction.

Wnt dysfunction is also involved in many types of cancer and therefore has been subject of much research.

The surprise came when I read that attempts are underway to “tune” Wnt signaling to control hair growth.  Why not autism?

This post is about tuning Wnt signaling to improve cognitive function and behavior.  This appears just as plausible as controlling hair growth.

The Wnt Signaling Pathways

Here is the Wikipedia explanation.

Wnt signaling pathway

The Wnt signaling pathways are a group of signal transduction pathways made of proteins that pass signals from outside of a cell through cell surface receptors to the inside of the cell. Three Wnt signaling pathways have been characterized: the canonical Wnt pathway, the noncanonical planar cell polarity pathway, and the noncanonical Wnt/calcium pathway. All three Wnt signaling pathways are activated by the binding of a Wnt-protein ligand to a Frizzled family receptor, which passes the biological signal to the protein Dishevelled inside the cell. The canonical Wnt pathway leads to regulation of gene transcription, the noncanonical planar cell polarity pathway regulates the cytoskeleton that is responsible for the shape of the cell, and the noncanonical Wnt/calcium pathway regulates calcium inside the cell. Wnt signaling pathways use either nearby cell-cell communication (paracrine) or same-cell communication (autocrine). They are highly evolutionarily conserved, which means they are similar across many species from fruit flies to humans.^[1][2]
Wnt signaling was first identified for its role in carcinogenesis, but has since been recognized for its function in embryonic development. The embryonic processes it controls include body axis patterning, cell fate specification, cell proliferation, and cell migration. These processes are necessary for proper formation of important tissues including bone, heart, and muscle. Its role in embryonic development was discovered when genetic mutations in proteins in the Wnt pathway produced abnormal fruit fly embryos. Later research found that the genes responsible for these abnormalities also influenced breast cancer development in mice.
The clinical importance of this pathway has been demonstrated by mutations that lead to a variety of diseases, including breast and prostate cancer, glioblastoma, type II diabetes, and others.^[3][4]

The Canonical Wnt pathway is dysfunctional in Autism

It is the canonical Wnt pathway that is dysfunction in autism and it is this same pathway plays a role in dendrite growth and suboptimal Wnt activity negatively affects the dendritic arbor.

A very thorough review of all the genetic evidence is provided in the following study:

A review of the evidence for the canonical Wnt pathway in autism spectrum disorders

Notably, the available genetic information indicates that not only canonical Wnt pathway activation, but also inhibition seems to increase autism risk. The canonical Wnt pathway plays a role in dendrite growth and suboptimal activity negatively affects the dendritic arbor. In principle, this provides a logical explanation as to why both hypo- and hyperactivity may generate a similar set of behavioral and cognitive symptoms.

The review highlights that, as we have seen before, some people with autism are hypo and some people are hyper; this means some people need Wnt signaling to be inhibited and other people need the opposite therapy.  The author points out that you really need some test to check which way you need your Wnt “tuned”.  

It sounds a bit like tuning the timing of the sparks inside your car engine, in the days before it was all electronic and self-tuning.  In theory you needed to measure the timing of the sparks with a special strobe light; but if you knew what you were doing you could just use your ears.  So in the same vein, you could make a small change to inhibit Wnt and see the result, if it made matters worse you just stop and go the other way.  As you will see later in this post, some of us are already tuning Wnt without even realizing it.

We have exactly the same issue with mGluR5, where you might need a positive/negative allosteric modulator to optimize brain performance.  Different variants of “autism” would be located either left or right of “top dead center”.

In that post we learnt that at MIT they are suggesting that errors in synaptic protein synthesis are behind several types of autism and that these errors can be corrected using either positive or negative stimulators of the receptor mGluR5.

Ketamine, Memantine, D-Cycloserin, Magnesium, Fenobam and yet more as Glutamatergic Modulators in Autism (and Fragile X)

For a more detailed understanding of Wnt signaling, see the paper below:-

Wnt signal transduction pathways

For Homer Simpson and others wanting more hair

Tuning Wnt signals for more or fewer hairs

Abnormal hair development and regeneration has been implicated in diseases of the skin (ie., hirsutism, alopecia, etc) or in open wounds when hair follicles are completely eliminated. To manage these clinical conditions, it is important to understand molecular pathways which regulate the number, size, growth and regeneration of hair follicles. Wnt signaling plays a fundamental role in this process. We need a deeper understanding so we can reliably adjust Wnt levels in existing follicles. This studies reviewed here have future translational value for skin regeneration following severe wound injuries or in the context of tissue engineering. Tuning the levels of Wnt ligands can directly modulate the number and growth of hairs. Using this new knowledge, we now know that Wnt activity can be modulated by adjusting the secretion of Wnt ligands, altering binding of ligands to receptors, inhibiting β-catenin translocation, or by regulating extra-follicular dermal Wnt and Wnt inhibitors.

How to tune Dendritic Spine Morphology

We have already encounter Brain-Derived Neurotropic Factor  (BDNF) in an earlier post.  You could think of BDNF as brain fertilizer.

Human Growth Factors, Autism and the Centenarian Nobel Laureate

“Older people and anyone with Retts Syndrome are likely to benefit from more NGF (Nerve Growth Factor).  In autism it appears possible that there was too much NGF and BDNF at a very early age, with levels then changing.  High levels of NGF and BDNF look a bad idea.  A lot more research is needed to understand what determines  NGF and BDNF levels.  It appears that BDNF may stay high in autism, but NGF levels.”

It has been shown that BDNF and Wnt signaling together regulate dendritic spine formation.

So, since in autism we have excess BDNF as the brain is developing, this might explain there are too many dendritic spines in autistic brains.  Too many spines and the wrong morphology (shape) would explain very many issues that have gone “wrong” in autistic brains.

Neurotrophin and Wnt signaling cooperatively regulate dendritic spine formation

Here, we show that Wnt signaling inhibition in cultured cortical neurons disrupts dendritic spine development, reduces dendritic arbor size and complexity, and blocks BDNF-induced dendritic spine formation and maturation. Additionally, we show that BDNF regulates expression of Wnt2, and that Wnt2 is sufficient to promote cortical dendrite growth and dendritic spine formation. Together, these data suggest that BDNF and Wnt signaling cooperatively regulate dendritic spine formation.

BDNF overexpression rapidly and robustly increases primary dendrite formation in cortical neurons (Horch et al., 1999; McAllister et al., 1997; Wirth et al., 2003). We reproduced this finding, and found that this increase was not blocked by overexpression of the Wnt inhibitors (Fig. S2), indicating that some aspects of BDNF modulation of dendrites remain intact in the presence of Wnt inhibitors. To further assess whether expression of the Wnt inhibitors impaired the signaling ability of BDNF, we analyzed autocrine induction of c-Fos expression by BDNF overexpression. c-Fos is an immediate early gene whose transcription is rapidly upregulated by BDNF (Calella et al., 2007; Gaiddon et al., 1996). We found that BDNF induced c-Fos expression was not reduced in neurons overexpressing any of the four Wnt inhibitors, suggesting that the ability of the inhibitors to interfere with BDNF-induced spine formation and spine head width expansion was not a result of decreased levels of BDNF signaling (Fig. S3).

Fig. 5

Wnt2 overexpression is sufficient to increase cortical dendrite length. (A) Representative cortical neurons expressing either EV or Wnt2. Quantification of the total dendrite length per neuron (B) and the number of dendritic endpoints per neuron (C) for ...

Fig. 6

Wnt2 overexpression increases dendritic protrusion density and influences spine shape on cortical neurons. (A) Representative dendritic segments of cortical neurons expressing either EV or Wnt2. (B) Quantification of dendritic protrusion density. (C) ...

Wnt inhibition and dendritic spine maturation

We found that a series of different Wnt signaling inhibitors were able to block BDNF-induced increases in dendritic spine density and dendritic spine head width

I think all this existing science really tells us a lot.

Back in the slow lane

In cancer research, decades have already been spent investigating Wnt signaling.

Wnt Signaling Inhibition: Will Decades of Effort Be Fruitful at Last?

Drugs that Enhance Wnt Signaling

Back in my world, with a little help from Google scholar, I rapidly find that drugs already exist that affect Wnt signaling.  Some very familiar names pop up.

Simvastatin Promotes Adult Hippocampal Neurogenesis by Enhancing Wnt/β-Catenin Signaling

SummaryStatins improve recovery from traumatic brain injury and show promise in preventing Alzheimer disease. However, the mechanisms by which statins may be therapeutic for neurological conditions are not fully understood. In this study, we present the initial evidence that oral administration of simvastatin in mice enhances Wnt signaling in vivo. Concomitantly, simvastatin enhances neurogenesis in cultured adult neural progenitor cells as well as in the dentate gyrus of adult mice. Finally, we find that statins enhance Wnt signaling through regulation of isoprenoid synthesis and not through cholesterol. These findings provide direct evidence that Wnt signaling is enhanced in vivo by simvastatin and that this elevation of Wnt signaling is required for the neurogenic effects of simvastatin. Collectively, these data add to the growing body of evidence that statins may have therapeutic value for treating certain neurological disorders.Simvastatin rescues cerebrovascular and memory-related deficits in mouse models of Alzheimer disease (AD) (Li et al., 2006; Tong et al., 2009, 2012), and recent meta-analysis of clinical studies concluded that statins provide a slight benefit in the prevention of AD and all-type dementia (Wong et al., 2013). While these effects have been attributed to reduction of inflammation, reduced oxidative stress, upregulated PI3K/AKT signaling, and enhanced neurogenesis, the mechanisms by which statins are beneficial in neurological disorders are not fully understood.Simva is under investigation for its potential therapeutic effects outside of hyperlipidemia treatment. While statins have been reported to enhance Wnt signaling in vitro, it was heretofore not known whether statins can enhance this pathway in vivo and in the context of neurogenesis. Here we provide evidence that oral simva treatment enhances Wnt signaling in the mammalian adult hippocampus. This is significant in that aside from lithium, no other clinically approved compound has been demonstrated to enhance Wnt signaling in the brain

You will find the element Lithium in your smart phone battery, but it is also a drug.

Lithium is useful in the treatment of bipolar disorder. Lithium salts may also be helpful for related diagnoses, such as schizoaffective disorder and cyclic major depression. The active part of these salts is the lithium ion Li⁺.

But, not surprisingly, Lithium has other effects, like activating Wnt signaling.

Lithium activates the Wnt and phosphatidylinositol 3-kinase Akt signaling pathways to promote cell survival in the absence of soluble survival factors.

Drugs that inhibit Wnt Signaling

There are drugs with the opposite effect, inhibiting Wnt signaling.

Verapamil Protects against Cartilage Degradation in Osteoarthritis by Inhibiting Wnt/β-Catenin Signaling

Abstract

In past years, the canonical Wnt/β-catenin signaling pathway has emerged as a critical regulator of cartilage development and homeostasis. FRZB, a soluble antagonist of Wnt signaling, has been studied in osteoarthritis (OA) animal models and OA patients as a modulator of Wnt signaling. We screened for FDA-approved drugs that induce FRZB expression and suppress Wnt/β-catenin signaling. We found that verapamil, a widely prescribed L-type calcium channel blocker, elevated FRZB expression and suppressed Wnt/β-catenin signaling in human OA chondrocytes. Expression and nuclear translocation of β-catenin was attenuated by verapamil in OA chondrocytes. Lack of the verapamil effects in LiCl-treated and FRZB-downregulated OA chondrocytes also suggested that verpamil suppressed Wnt signaling by inducing FRZB. Verapamil enhanced gene expressions of chondrogenic markers of ACAN encoding aggrecan, COL2A1 encoding collagen type II α1, and SOX9, and suppressed Wnt-responsive AXIN2 and MMP3 in human OA chondrocytes. Verapamil ameliorated Wnt3A-induced proteoglycan loss in chondrogenically differentiated ATDC5 cells. Verapamil inhibited hypertrophic differentiation of chondrocytes in the explant culture of mouse tibiae. Intraarticular injection of verapamil inhibited OA progression as well as nuclear localizations of β-catenin in a rat OA model. We propose that verapamil holds promise as a potent therapeutic agent for OA by upregulating FRZB and subsequently downregulating Wnt/β-catenin signaling.

Repositioning verapamil—for Wnt of an OA treatment

The river blindness drug Ivermectin and related macrocyclic lactones inhibit WNT-TCF pathway responses in human cancer

AbstractConstitutive activation of canonical WNT-TCF signaling is implicated in multiple diseases, including intestine and lung cancers, but there are no WNT-TCF antagonists in clinical use. We have performed a repositioning screen for WNT-TCF response blockers aiming to recapitulate the genetic blockade afforded by dominant-negative TCF. We report that Ivermectin inhibits the expression of WNT-TCF targets, mimicking dnTCF, and that its low concentration effects are rescued by direct activation by TCF^VP16. Ivermectin inhibits the proliferation and increases apoptosis of various human cancer types. It represses the levels of C-terminal β-CATENIN phosphoforms and of CYCLIN D1 in an okadaic acid-sensitive manner, indicating its action involves protein phosphatases. In vivo, Ivermectin selectively inhibits TCF-dependent, but not TCF-independent, xenograft growth without obvious side effects. Analysis of single semi-synthetic derivatives highlights Selamectin, urging its clinical testing and the exploration of the macrocyclic lactone chemical space. Given that Ivermectin is a safe anti-parasitic agent used by > 200 million people against river blindness, our results suggest its additional use as a therapeutic WNT-TCF pathway response blocker to treat WNT-TCF-dependent diseases including multiple cancers.

Effects of Caffeic Acid Phenethyl Ester in Wnt/β-Catenin Signaling Pathway on Human Neuroglioma

Previous studies have revealed that its anti-tumor function could be attributed to its ability to suppress the abnormal Wnt/β-catenin signaling pathway

What about hair loss/gain?

To quote from  the previous study on hair loss gain:-

“Using this new knowledge, we now know that Wnt activity can be modulated by adjusting the secretion of Wnt ligands, altering binding of ligands to receptors, inhibiting β-catenin translocation, or by regulating extra-follicular dermal Wnt and Wnt inhibitors.”

We have now learnt that the drug Verapamil is thought to be a Wnt inhibitor.  So it would be fair to assume that hair loss would be reported as a side effect of using Verapamil.  Indeed it is.

Dermatologic

Dermatologic side effects have included rash (up to 1.4%). Diaphoresis has been reported with intravenous verapamil. Arthralgia and rash, exanthema, hair loss, hyperkeratosis, macules, sweating, urticaria, Stevens-Johnson syndrome, and erythema multiforme have been reported during open trials/postmarketing experience.

What about Statins and hair?

So many millions of people take statins, of course somebody would claim it causes hair loss (alopecia).  I think it should cause hair gain.  As with Verapamil the effect on the hair growth would be much greater if it was applied to the skin and not taken orally.  Maybe older people would not go to the doctor to complain about hair gain?

Do statins cause alopecia?

Summary

·        As hair loss is a generally accepted male characteristic, drug-induced alopecia may be mistaken as part of a natural process and therefore under reported.

·        There have been reports of alopecia associated with the use of all UK licensed statins but there is insufficient data to confidently attribute hair loss to statin use.

·        Case studies suggest an association but as yet there is insufficient information to suggest a mechanism, make comparisons of the individual incidence of alopecia between the various statins or propose a class effect.

·        The greatest number of reports of alopecia is for simvastatin but this may be related to a greater market share or length of time on market.

It would seem that enough people lose hair from Verapamil for it to be a published side effect.  The same is not true for statins and I think hair loss may be coincidental.

But, maybe too much and too little Wnt signaling cause hair loss ?

Recall earlier in this post that Hans Otto Kalkman suggested that both too much and too little Wnt might cause similar behavioral and cognitive symptoms.  Perhaps the same is true with hair growth.

The canonical Wnt pathway plays a role in dendrite growth and suboptimal activity negatively affects the dendritic arbor. In principle, this provides a logical explanation as to why both hypo- and hyperactivity may generate a similar set of behavioral and cognitive symptoms.

For optimal hair growth perhaps there is an optimal amount of Wnt signaling? 

That might explain why a small number of people find Wnt inhibitors (Verapamil) and drugs that enhance Wnt (statins) cause hair loss.

That might mean that people with very full hair have optimal Wnt signaling?

So advise Homer Simpson to find out whether his Wnt signaling is hyper or hypo.  Then he might find either simvastatin or verapamil brings back his full head of hair.

Wnt signaling and Diabetes

Yet again we find another connection between Diabetes and autism.

In the pancreas  β-cells produce insulin. In diabetics these β-cells get destroyed.  It appears that Wnt signaling is involved in controlling these β-cells.  It has been proposed that they could be protected via this pathway.

Role of Wnt signaling in the development of type 2 diabetes.

 

Abstract

Type 2 diabetes is characterized by insulin resistance, insulin deficiency, and hyperglycemia. Susceptibility to type 2 diabetes has been linked to Wnt signaling, which plays an important role in intestinal tumorigenesis. Carriers of variants of the transcription factor 7-like 2 gene, an important component of the Wnt pathway, are at enhanced risk for developing type 2 diabetes. The modulation of proglucagon expression by Wnt activity may partially explain the link between Wnt signaling and diabetes, and one of the transcriptional and processing products of the proglucagon gene, the glucagon-like peptide-1 (GLP-1), exhibits a wide variety of antidiabetogenic activities. GLP-1 stimulates Wnt signaling in pancreatic beta cells, enhancing cell proliferation; thus, positive feedback between GLP-1 and Wnt signaling may result in increased proliferation, and suppressed apoptosis, of pancreatic cells. Since beta-cell protection is a potential treatment for type 2 diabetes, stimulation of Wnt activity may represent a valid therapeutic approach.

Wnt signaling: relevance to β-cell biology and diabetes

Here, we review emerging new evidence that Wnt signaling influences endocrine pancreas development and modulates mature β-cell functions including insulin secretion, survival and proliferation. Alterations in Wnt signaling might also impact other metabolic tissues involved in the pathogenesis of diabetes, with TCF7L2 proposed to modulate adipogenesis and regulate GLP-1 production. Together, these studies point towards a role for Wnt signaling in the pathogenesis of type 2 diabetes, highlighting the importance of further investigation of this pathway to develop new therapies for this disease.

Future Prospects of Wnt-Targeted Therapy for Treatment of Type 2 Diabetes

As with autism and cancer, the people with diabetes are also perhaps not benefiting from the latest science.

Preventing β-Cell Loss and Diabetes With Calcium Channel Blockers

Oral verapamil administration prevents β-cell apoptosis and STZ-induced diabetes.

The End.