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.

Mounting Evidence Regarding Autism, Neurofibromatosis and PAK1

When I google “autism” and “PAK1”, I keep seeing my own posts come up.  This is beginning to be a regular occurrence, when I research an idea.  Google “verapamil autism”, “clonazepam autism” “bumetanide autism” and even “NAC autism”, the same thing happens.

So it is nice to have some further studies that also show the possible importance of PAK1 in treating autism.  This time it is from the University of Indiana and more precisely, Anantha Shekhar, Professor of Psychiatry at the School of Medicine.

We have the study’s abstract and the more people-friendly press release.

Social learning and amygdala disruptions in Nf1 mice are rescued by blocking p21-activated kinase (PAK1)

Abstract

Children with neurofibromatosis type 1 (NF1) are increasingly recognized as having a high prevalence of social difficulties and autism spectrum disorders (ASDs). We demonstrated a selective social learning deficit in mice with deletion of a single Nf1 allele (Nf1^+/−), along with greater activation of the mitogen-activated protein kinase pathway in neurons from the amygdala and frontal cortex, structures that are relevant to social behaviors. The Nf1^+/− mice showed aberrant amygdala glutamate and GABA neurotransmission, deficits in long-term potentiation and specific disruptions in the expression of two proteins that are associated with glutamate and GABA neurotransmission: a disintegrin and metalloprotease domain 22 (Adam22) and heat shock protein 70 (Hsp70), respectively. All of these amygdala disruptions were normalized by the additional deletion of the p21 protein-activated kinase (Pak1) gene. We also rescued the social behavior deficits in Nf1^+/− mice with pharmacological blockade of Pak1 directly in the amygdala. These findings provide insights and therapeutic targets for patients with NF1 and ASDs.

Here is the very informative and readable press release.

 

Blocking one gene could aid social behavior in some forms of autism, IU scientists report

INDIANAPOLIS -- Blocking a single gene that is active in the brain could provide a means to lessen behavioral problems among children with a common genetic disease, many of whom are also diagnosed with an autism disorder, according to researchers at the Indiana University School of Medicine.

The genetic disorder, neurofibromatosis type 1, is one of the most common single-gene diseases, affecting about 1 in 3,000 children worldwide. Symptoms can range from café-au-lait spots on the skin to tumors that are disfiguring or that can press dangerously against internal organs.

"Physicians are increasingly recognizing that many children with the disorder have social and behavioral difficulties, and as many as one in five cases of autism may be associated with the same biochemical defects seen in neurofibromatosis type 1," said Anantha Shekhar, M.D., Ph.D., Raymond E. Houk Professor of Psychiatry at the IU School of Medicine.

The researchers used a mouse model of neurofibromatosis, examining both behavioral differences from normal mice and biochemical differences in the animals' brains, particularly in the amygdala, a brain structure associated with social behavior and emotional regulation.

Reporting their work in the journal Nature Neuroscience, the researchers found that the neurofibromatosis model mice had problems with long term social learning -- remembering important social cues involving interactions with other mice. Tests also showed that neurochemical pathways between structures of the brain involved with social behavior were disrupted by the neurofibromatosis mutation.

However, blocking the activity of another gene -- called Pak1, which is involved with those neurochemical pathways -- improved the social behaviors of the mice. Mice bred to have both the neurofibromatosis mutation and the deletion of the Pak1 gene engaged in social behavior similar to normal mice. In addition, mice with the neurofibromatosis mutation that were injected with a compound known to block Pak1 gene activity had normal social behavior restored.

"These findings could lead to novel approaches to treating behavioral problems that are seen in NF1 patients and some patients with autism spectrum disorders," said D. Wade Clapp, M.D., Richard L. Schreiner Professor of Pediatrics at the IU School of Medicine.

Implications

The researchers from Indiana are suggesting that 20% of people with autism may have the same dysfunction as the very much rarer condition of neurofibromatosis type 1.  Those 20% are likely to benefit from treatments shown to be effective in NF-1.

How do you know whether you are in the 20%?  A little genetic testing might tell you, or maybe not (see below).

In the absence of such testing, you could possibly deduce something from looking at the comorbidities.

It might seem odd that NF-1, a rare disorder affecting 1 in 3,000 children could share its underpinnings with 20% of children with autism, which would roughly equate to 6 in 3,000 children.

This reminds me of a question I raised earlier:-

Just How Rare are the Known Genetic Causes of Autism?

In that post it became clear that you can have a partial dysfunction of a “rare” genetic disorder.  I wonder if that partial dysfunction will show up on today’s genetic tests.

Comorbidities

The comorbidities of autism that most intrigue me are asthma, allergies and ulcerative colitis.  I have a suspicion that they are all linked by mast cell degranulation and further, that what is underlying autism is promoting mast cells to degranulate.

A recent study showed how PAK1 is involved in modulating mast cell degranulation:-

A Pak1-PP2A-ERM signaling axis mediates F-actin rearrangement and degranulation in mast cells

 

And another one:- 

PAK1 AS A THERAPEUTIC TARGET

Fortunately, the effects of PAK1-deficiency on the immune system have a very encouraging up-side. As demonstrated by otherwise relatively healthy PAK1-/- mice, Pak1 is critical for disassembly of cortical F-actin upon allergen stimulation, and PAK1 deficiency prevents the release of pro-inflammatory molecules from the granules of mast cells during the IgE-associated allergic responses

I have already shown the effectiveness of Verapamil as a therapy for autism and mast cell degranulation.  I suspect that a further improvement may follow with a potent PAK1 inhibitor.

I think the Indiana research also points in the same direction.

There is also the issue of malformed dendritic spines, which will be fully addressed in a later post.  This appears in autism and schizophrenia and may explain much of why autistic brains function differently to other peoples.  It is thought that this malformation is also linked to PAK1.

So while treating mast cell degranulation will help some people’s autism, you could also go one step backwards up the chain and address the signal that was prompting them to degranulate.  This same signal may trigger an unrelated damaging cascade of events elsewhere in the brain.

Which PAK1 inhibitor?

In earlier post we saw that the choices of PAK1 inhibitor are:-

1.     Experimental drugs still under development by Afraxis, the MIT spin-off  

2.     Ivermectin, an old anti-parasite drug, used with some success by fringe alternative doctors in the US.  At least one reader of this blog is a fan of Ivermectin for autism.
 
3.     Certain types of Propolis, like the one containing CAPE (Caffeic Acid Phenethyl Ester) that comes from New Zealand
 

The question remains whether the Propolis is potent enough to have the same effect as Ivermectin.  In the NF-1 and NF-2 community, opinion is split as to whether Propolis can shrink existing tumours.  This issue of stopping new tumours developing, versus shrinking existing ones does seem to crop up quite often in cancer research as well.  Drugs are, not surprisingly, most effective when used very early on.

Ivermectin cannot be used long term continuously, since it is toxic.  It can be used “on and off” for decades as an anti-parasite therapy.

Crossing the Blood Brain Barrier

Once question arose in an earlier post as to how Ivermectin could be effective in autism, since it does not readily cross the blood brain barrier.  According to the experts it does not have to, see below:-

PAK1 AS A THERAPEUTIC TARGET

11. Expert opinion: Is PAK1 a suitable target for therapy?

As discussed above, there is growing evidence that PAKs are involved in the phenomena that are clinically significant for various cardio-vascular disorders, but the specificity of PAK1 involvement is still uncertain. Studies indicate that even closely related PAKs (e.g. PAK1 and PAK2) have non-identical sets of substrates. The issue is further complicated because of the multiple and sometimes opposing roles of PAKs in these processes and certainly merits further investigation.

The reports on the involvement of PAK1 in various diseases of the brain indicate that both up- and down-regulation of this enzyme may be associated with pathological changes. This, along with the uncertainty about the relative contribution of other isoforms, clouds the prospect of targeting PAK1 for therapeutic intervention in these conditions. Furthermore, these observations necessitate a close attention to the affects that any anti-PAK therapy targeted at other organs might have on the nervous system, including the cognitive functions and the memory. In this regard, failure of an anti-PAK1 agent to penetrate the blood-brain barrier may not be a detriment to its therapeutic utility. Similarly complicated is the question of PAK1 targeting in infections: while it may partially attenuate certain viruses, it would also negatively impact some functions of the immune system. In fact, the recent report of PAK1-deficient animals having IgE-mediated responses to allergens may indicate that, at least, for such acute life-threatening conditions as anaphylaxis the benefits of suppressing PAK1 may outweigh the risks.

My PAK-1 inhibitor Trial

I am practicing what I preach, so to speak.  Only once the pollen allergy season is well and truly over, will I trial my PAK-1 inhibitor.  I want a genuine result, free from external effects, like degranulating mast cells.

Since Ivermectin is known to react with other drugs in my PolyPill, I will be using the Propolis from New Zealand.