Treatable Human Endogenous Retroviruses (HERVs) in Multiple Sclerosis (MS), ALS and other Neurological Diseases – an Enemy from Within?

  

A microglial cell, labelled in green, contacts and attacks a myelinated axon (in red). In the presence of the pHERV-W envelope protein, this interaction leads to axonal injury. The blue structures are cell nuclei. Credit: HHU / Joel Gruchot / Patrick Küry

  

It is surprising that only about 2% of human DNA encodes the 20,000 or so genes we all have.  The other 98% used to be called junk DNA.

About 8% of your DNA is made up of Endogenous retroviruses (ERVs) that have been picked up during evolution and most of which have been inactivated and can indeed be regarded as junk. Some of these old viruses that became part of human DNA remain fully functional, can be activated; they are implicated in disease ranging from Multiple Sclerosis (MS), to cancer, to schizophrenia and ALS (motor neuron disease).

The best documented ERV is the one that affects some people with MS, it is called HERV-W  (the H is for Human).  Only in the presence of a protein encoded by this virus can the microglia cells attack the myelin layer on axons.  In this kind of MS, if you could switch off the HERV-W virus you would solve the remyelination problem.

The thing to remember is that MS is a family of conditions and HERV-W may only be relevant to specific sub-types.  The recent research (see below) produced the image at the start of today’s post, where we actually see the microglia (green) mistakenly attacking the healthy myelin on axons (red).

Multiple sclerosis: Endogenous retrovirus HERV-W key to nerve tissue damage

As outlined by first author Dr. David Kremer, the envelope (ENV) protein of the pathogenic human endogenous retrovirus type W (pHERV-W) was found to be a major contributor to nerve damage in MS. In collaboration with research teams in the U.S. and Canada, the authors demonstrated that the ENV protein drives CNS resident microglial cells to contact and damage myelinated axons.                                                                                      

pHERV-W envelopeprotein fuels microglial cell-dependent damage of myelinated axons in multiplesclerosis

There is a broad repertoire of immunomodulatory drugs that effectively treat the inflammatory aspects of relapsing multiple sclerosis (MS). However, axonal degeneration, which occurs mainly in progressive MS, is still not understood and cannot be treated pharmaceutically. As it is the major factor contributing to clinical disability in MS, it represents an unmet clinical need. A recently completed phase IIb study has demonstrated that anti-pathogenic human endogenous retrovirus type W (pHERV-W) envelope protein (ENV) treatment results in a significant decrease of neurodegenerative brain atrophy in treated MS patients. For these results, the work presented here offers an explanation by demonstrating that, via myeloid cells, pHERV-W ENV directly harms axons.

Axonal degeneration is central to clinical disability and disease progression in multiple sclerosis (MS). Myeloid cells such as brain-resident microglia and blood-borne monocytes are thought to be critically involved in this degenerative process. However, the exact underlying mechanisms have still not been clarified. We have previously demonstrated that human endogenous retrovirus type W (HERV-W) negatively affects oligodendroglial precursor cell (OPC) differentiation and remyelination via its envelope protein pathogenic HERV-W (pHERV-W) ENV (formerly MS-associated retrovirus [MSRV]-ENV). In this current study, we investigated whether pHERV-W ENV also plays a role in axonal injury in MS. We found that in MS lesions, pHERV-W ENV is present in myeloid cells associated with axons. Focusing on progressive disease stages, we could then demonstrate that pHERV-W ENV induces a degenerative phenotype in microglial cells, driving them toward a close spatial association with myelinated axons. Moreover, in pHERV-W ENV-stimulated myelinated cocultures, microglia were found to structurally damage myelinated axons. Taken together, our data suggest that pHERV-W ENV-mediated microglial polarization contributes to neurodegeneration in MS. Thus, this analysis provides a neurobiological rationale for a recently completed clinical study in MS patients showing that antibody-mediated neutralization of pHERV-W ENV exerts neuroprotective effects.

Relapsing-Remitting Multiple Sclerosis (RRMS)

Most MS starts out as so-called Relapsing-Remitting Multiple Sclerosis (RRMS) and so is the focus of much research. An antibody called GNbAC1 has been developed to specifically target the protein MSRV-Env that is produced by the old human endogenous retrovirus type W.

GNbAC1 for RRMS 

GNbAC1 is an antibody designed to specifically target and bind to MSRV-Env, preventing it from inducing an immune response.

In vitro and in vivo studies showed that GNbAC1 neutralizes MSRV-Env, reducing the inflammatory response and allowing the remyelination repair process to restart.

I think this is an excellent example of how to translate complicated science into a practical therapy.  I just hate to think how much money this therapy will cost.

Or just Antivirals?

I did wonder about a less expensive therapy to block the MSRV-Env protein from activating microglia to destroy myelin.  Why not use a relatively cheap antiviral drug to dampen the virus itself, so it does not make the harmful protein?

Unlike most antibiotics, antiviral drugs do not destroy their target pathogen; instead they inhibit their development.

Antiviral drugs normally have to be developed to target a specific virus, but you might just get lucky with an existing drug.

In the case of HIV, a combination of three drugs is used TDF (tenofovir), EFV (efavirenz) and either 3TC (lamivudine) or FTC (emtricitabine).  This therapy has been hugely successful.

The anti-herpes antivirals include valacyclovir (Valtrex), famciclovir (Famvir), and acyclovir (Zovirax).

In the case of Multiple Sclerosis, I did find a study that used acyclovir.  It did not cure the condition, but it did significantly reduce exacerbations.

                                                       

Trials of antivirals in the treatment of multiple sclerosis

I am afraid nobody seems to want a cheap drug for MS, when the other only partially effective ones can cost $50,000 a year. Acyclovir is much more expensive in the US than elsewhere but nothing like the price of the new MS drugs.

It may of course be a coincidence that Acyclovir reduces exacerbations in MS and may involve an entirely different mechanism.


Human endogenous retroviruses (HERVs) beyond MS

Drugs for MS are a huge business for pharmaceutical companies and this is why the research is advanced.

HERVs have been implicated in ALS (motor neuron disease) and schizophrenia.  There is even some research on HERVs and autism.

It is usually the Herpes virus that gets mentioned in the context of autism. It is probably one of hundreds of possible triggers that, when combined with other “hits” and genetic predispositions, may lead to autism.

Any virus can affect gene expression and so any virus has the potential to cause harm to a developing brain.  This is often all "autism" is, the result of some damage at a critical point in the brain's development. That same event in a teenager does no long term harm. 

Herpes virus may be a trigger for autism

“We’re not saying that HSV-2 is responsible for infecting the [fetal] brain and causing autism,” stresses senior author Ian Lipkin, an infectious disease expert and epidemiologist at Columbia. Indeed, fetal infection with HSV-2 is so serious that it frequently leads to miscarriages or stillbirths. Rather, Lipkin suspects that HSV-2 is just one among many environmental insults that, when they arrive at a vulnerable point in fetal development in women predisposed to damaging reactions, may trigger ASD in the fetus. That idea comports with a body of previous work, like this Swedish study that found that the hospitalization of a woman for any kind of infection during pregnancy increased the risk of the baby developing ASD by 30%.

Some scientists are skeptical that inflammatory molecules alone could be responsible, in part because of the big changes in brain structure that arise in autistic children in the first 2 years of life, just as symptoms of ASD emerge. For instance, a study published in Nature last week documents abnormal overgrowth of the surface of the brain in 6- to 12-month-old babies who go on to be diagnosed with ASD.

Are the 'viral' agents of MS, ALS and schizophrenia buried in our genome?

Viruses hid themselves in your ancestors' DNA; now they're waking up

What if the missing 'environmental' factor in some of our deadliest neurological diseases were really written in our genome? Researchers explain how viruses ended up in our DNA -- and what puts them in the frame in unsolved diseases like multiple sclerosis.

The enemy within

A whopping 8% of our DNA comes from viruses. Specifically, ones called retroviruses -- not because they're old, but because they reverse the normal process of reading DNA to write themselves into their host's genome.

Retroviruses are old though: they began merging with our earliest, primordial ancestors millions of years ago. Over the millennia, most of their remnants in our DNA -- known as human endogenous retroviruses or HERVs -- have been silenced by mutations. Others, which had evolved to fend off rival viruses, formed the prototypical immune system and to this day protect us from infection.

However, HERVs might also be the missing causative link in major 'unsolved' neurological diseases.

"HERVs have been implicated in the onset and progression of multiple sclerosis [MS], amyotrophic lateral sclerosis [ALS] and schizophrenia [SCZ]," says senior author Prof. Patrick Kuery. "Dormant HERVs can be reactivated by environmental factors such as inflammation, mutations, drugs, or infection with other viruses, so could provide a mechanism for their well-established epidemiological link to these disorders."

Full paper: -

Neural Cell Responses Upon Exposure to Human Endogenous Retroviruses

Human endogenous retroviruses (HERVs) are ancient retroviral elements, which invaded the human germ line several million years ago. Subsequent retrotransposition events amplified these sequences, resulting in approximately 8% of the human genome being composed of HERV sequences today. These genetic elements, normally dormant within human genomes, can be (re)-activated by environmental factors such as infections with other viruses, leading to the expression of viral proteins and, in some instances, even to viral particle production. Several studies have shown that the expression of these retroviral elements correlates with the onset and progression of neurological diseases such as multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). Further studies provided evidence on additional roles for HERVs in schizophrenia (SCZ). Since these diseases are still not well understood, HERVs might constitute a new category of pathogenic components that could significantly change our understanding of these pathologies. Moreover, knowledge about their mode of action might also help to develop novel and more powerful approaches for the treatment of these complex diseases. Therefore, the main scope of this review is a description of the current knowledge on the involvement of HERV-W and HERV-K in neurological disease specifically focusing on the effects they exert on neural cells of the central nervous system.

Importantly, several studies were able to show that inflammation plays a major role in HERV activation 

SCZ is a complex neuropsychiatric disorder characterized by a variety of cognitive, emotional, and perceptual disturbances. Pathophysiologically, SCZ features decreased brain volume, loss of myelin, and altered astrocyte function (Archer, 2010). In contrast to MS and ALS, both HERV-W and HERV-K have been weakly linked to SCZ based on PCR amplification from CSF and post-mortem brains as well as on protein antigenemia (Yolken et al., 2000; Karlsson et al., 2001; Frank et al., 2005; Perron et al., 2008), while another study revealed upregulation of HERV-W ENV transcripts in plasma samples of SCZ patients (Huang et al., 2011). Moreover, a new study provides evidence that, in early stages of this disease, HERV-K methylation in peripheral blood is reduced (Mak et al., 2019). Of note, these observations contradict an earlier report suggesting that HERV-W expression is reduced in SCZ patients (Weis et al., 2007). The disparity between these reports may reflect different experimental approaches or a differential use of anti-psychotic medications in SCZ patients.

We here present collected evidence that endogenous retroviral elements acting either as viral particles or via their proteins influence neural cells in the context of degenerative CNS diseases. Once thought to be primarily involved in cell transformation (Grabski et al., 2019) and inflammation (Perron and Lang, 2010), emerging data suggests a direct role of these elements in glial and neuronal injury, which in fact goes beyond previous descriptions on the activity of a gliotoxin (Menard et al., 1998). In light of additional observations on the role of ERVs in regulating stem cell potential and fate acquisition (Gautam et al., 2017), the findings describing impacts on committed or mature cells of the CNS are probably not too surprising but warrant future investigations, even more so since neural stem cells are also involved in brain pathology and regeneration. Moreover, the currently still unmet clinical need to effectively treat neurodegeneration necessitates novel therapeutic approaches. Whether similar mechanisms also apply to activation of transposable elements implicated in, for example, chronic fatigue syndrome (CFS; Almenar-Perez et al., 2019) and to what degree currently used neutralizing antibodies can be exploited in order to prevent neural cell activation and/or neurodegeneration needs to be elucidated in the future. In this regard, it remains to be shown whether HERV-employed signaling pathways and epigenetic silencing mechanisms can be used for biomedical translation.

                        

Figure 1 HERV-mediated effects on neural cells. This illustration summarizes origin and observed molecular effects of HERW-W and HERV-K on cells of the central nervous system. Arrow starting points indicate cellular sources of HERV particles or proteins (red dots), whereas arrowheads point to influenced cell types. Modulated processes are shown in gray boxes, and regulated molecules are highlighted in red next to each cell type. The question mark next to TDP-43 refers to its postulated regulation in neurons. Whether microglia and astroglia respond to HERVs in an auto- and/or paracrine way and whether neurons react to internal and/or extracellular HERVs remains to be shown. OPCs: oligodendroglial progenitor cells; NO: nitric oxide; CRP: C-reactive protein; BDNF: brain-derived neurotrophic factor; DRD3: dopamine receptor D₃; TRPC3: short transient receptor potential channel 3; DISC1: disrupted in schizophrenia 1; TDP-43: TAR DNA-binding protein 43.

                                  

Human Endogenous Retroviruses in Neurological Diseases.

HERVs, retroviral sequences integrated into the genome during evolution, are now known to represent 8% of the human genome.

These were recently shown to comprise copies that retain potential to express retroviral proteins or particles, and can be abnormally expressed in autoimmune, neurodegenerative, chronic inflammatory diseases, and cancer.

Environmental factors such as specific viral infections were shown to potently activate HERVs under tissue-specific and temporal conditions.

Of several diseases in which abnormal activation and expression of HERV proteins have been reported, studies over recent decades have led to a proof of concept that HERVs play a key role in the pathogenesis of MS and ALS.

HERV-W and HERV-K Env proteins induce pathogenic effects in vitro and in vivo that are relevant to the pathognomonic features of these diseases.

These endogenous retroviruses are potential novel therapeutic targets that are now being addressed with innovative therapeutic strategies in clinical trials.

The causes of multiple sclerosis and amyotrophic lateral sclerosis have long remained elusive. A new category of pathogenic components, normally dormant within human genomes, has been identified: human endogenous retroviruses (HERVs). These represent ∼8% of the human genome, and environmental factors have reproducibly been shown to trigger their expression. The resulting production of envelope (Env) proteins from HERV-W and HERV-K appears to engage pathophysiological pathways leading to the pathognomonic features of MS and ALS, respectively. Pathogenic HERV elements may thus provide a missing link in understanding these complex diseases. Moreover, their neutralization may represent a promising strategy to establish novel and more powerful therapeutic approaches.

HERVs Expression in Autism Spectrum Disorders

Results

The percentage of HERV-H and HERV-W positive samples was higher among ASD patients compared to HCs, while HERV-K was similarly represented and HERV-E virtually absent in both groups. The quantitative evaluation shows that HERV-H and HERV-W are differentially expressed in the two groups, with HERV-H being more abundantly expressed and, conversely, HERV-W, having lower abundance, in PBMCs from ASDs compared to healthy controls. PMBCs from ASDs also showed an increased potential to up-regulate HERV-H expression upon stimulation in culture, unlike HCs. Furthermore we report a negative correlation between expression levels of HERV-H and age among ASD patients and a statistically significant higher expression in ASD patients with Severe score in Communication and Motor Psychoeducational Profile-3.

Conclusions

Specific HERV families have a distinctive expression profile in ASD patients compared to HCs. We propose that HERV-H expression be explored in larger samples of individuals with autism spectrum in order to determine its utility as a novel biological trait of this complex disorder.

Transcriptional activity of human endogenous retrovirus in Albanian children with autism spectrum disorders

Recent studies suggest that autism spectrum disorders (ASD) result from interactions between genetic and environmental factors, whose possible links could be represented by epigenetic mechanisms. Here, we investigated the transcriptional activity of three human endogenous retrovirus (HERV) families, in peripheral blood mononuclear cells (PBMCs) from Albanian ASD children, by quantitative real-time PCR. We aimed to confirm the different expression profile already found in Italian ASD children, and to highlight any social and family health condition emerging from information gathered through a questionnaire, to be included among environmental risk factors. The presence of increased HERV-H transcriptional activity in all autistic patients could be understood as a constant epigenetic imprinting of the disease, potentially useful for early diagnosis and for the development of effective novel therapeutic strategies.

Overall, the data obtained in the present study lead us to further support the hypothesis that HERV transcriptional activity is influenced by all the factors mentioned above. Additional work is required to determine if HERV-H expression could be proposed as a biological marker, useful for early detection of children at high risk for ASD, before the appearance of clinical symptoms and for the development of effective new therapeutic strategies. To this end, an in-depth characterization of the potential role of HERV-H in ASD is the major objective of a study currently in progress in murine models. Currently, up to 2% of children worldwide are estimated to be diagnosed with an ASD (Pedersen et al., 2014) and the consistent increment in the prevalence of ASD is considered a pressing challenge for the global public health system. Because children represent more than a third of the Albanian population (Albanian Institute of Statistics 2011) autism is a serious socio-economic problem and its early diagnosis could represent a significant improvement in the treatment of the disease. In fact, if the autistic condition is diagnosed early, a growing repertoire of evidence-based therapies can be applied to give children the best possible chance of life.

Etiotropic and Pathogenetic Therapy of Autism Spectrum Disorder: Case Series of 6 Children

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that reveals itself by social communication problems, restrictive/repetitive behavior, and language impairment. ASD is a growing problem in the USA and in the world with no commonly-accepted etiology resulting in the absence of effective methods of treatment. Based on more than 80 scientific publications we are proposing the following understanding of ASD: it is a genetic disorder, in which some changes in DNA are resulting from a congenital mother to fetus transmitted infection and maternal immune activation. The infections and maternal immune activation result in oxidative stress and production of pro-inflammatory cytokines and other mediators. Based on this understanding, we developed a method of long-term etiotropic and pathogenetic therapy tailored to major chronic/latent infections, inflammation and immune system aberration. We present six cases of ASD treatment, which included the antiviral medication Valacyclovir and five nutritional supplements. The presented results are based on five cycles of treatment continued for 5 months. In all six cases the treatment resulted in social communication skills and behavioral improvements well as positive changes in the physical and psychological conditions. These improvements covariated with a tendency to normalization of blood and immune parameters. Social communication skills, behavioral, physical and psychological improvements also positively affected parents whose subjected quality of life increased over course of the treatment. According to parents of these children, the proposed treatment had superior efficacy compared to other types of treatment that their children underwent before.

Valacyclovir improves cognition in bipolar patients

A 4-month course of the oral antiviral agent valacyclovir boosted cognition in herpes simplex virus-1–seropositive patients with bipolar disorder and cognitive impairment in a randomized, double-blind placebo-controlled clinical trial.

Anti herpes Virus–Specific Treatment and Cognition in Schizophrenia: A Test-of-Concept Randomized Double-Blind Placebo-Controlled Trial

Objective

To test our hypothesis that valacyclovir, an antiherpes virus–specific medication, added to antipsychotics (APs) would improve cognitive performance and psychopathology among schizophrenia subjects exposed to neurotropic herpes simplex virus, type 1 (HSV1).

Methods

Using a double-blind placebo-controlled design, we randomized 24 HSV1-seropositive schizophrenia subjects to receive either valacyclovir (n = 12) or placebo (n = 12) for 18 weeks in addition to stable doses of APs. Valacyclovir dose was stabilized at 1.5 g twice daily orally. At each visit, subjects were evaluated for severity of psychopathology and side effects using standardized scales and a study-specific semistructured checklist. A computerized neurocognitive battery validated on both schizophrenia and healthy subjects was administered at baseline and follow-up. Intent-to-treat analysis, using linear regression models that included all randomized subjects, were used to examine differential changes in cognition and psychopathology scores over 18 weeks between valacyclovir and placebo, accounting for placebo response.

Results

Valacyclovir group improved in verbal memory, working memory, and visual object learning compared with placebo group. The effect sizes (Cohen’s d) were 0.79 for working memory, 1.14 for immediate verbal memory, and 0.97 for the visual object learning. Psychotic symptom severity did not improve.

Conclusions

Supplemental valacyclovir may alleviate impairments in cognitive domains that are often observed in schizophrenia but not psychotic symptoms in those exposed to HSV1. If replicated, this approach could provide a novel strategy to treat cognitive impairments in a subgroup of schizophrenia subjects who can be reliably identified using a blood test.

Conclusion

There is a great deal going on in the world of MS research and if you have MS you might as well consider becoming an early adopter.

As expected, the research on how these old viruses, that should be dormant in our DNA, might play a role in autism is not very advanced.

Some people with autism do take antiviral drugs and I think their caregivers think this relates to a virus they have acquired recently or comes from the mother. Perhaps it is an unidentified virus from that 8% of your DNA that has become activated?

In MS the story is complex but now we know for sure what the virus is, where it came from and what it does. You can defeat it with a tailor-made antibody called GNbAC1 or perhaps just beat it down a little with the common antiviral drug Acyclovir.

Note that antiviral drugs each only have an effect on certain types of virus.

Do HERVs really materially affect some people with autism, and its big brothers bipolar and schizophrenia? There is some limited evidence that they may.

People who report that their children with autism do indeed improve on an antiviral drug are unlikely to ever know which virus was the problem and it may not be the one they thought it was, but it is not a crazy idea.  If it reduces the symptoms of autism without causing troubling side effects, why not?  It is going to work for most autism? Probably not.

For people with Multiple Sclerosis (MS) the science is clear and unambiguous, you need to wipe out the protein called MSRV-Env.

As far as this blog is concerned, we already covered antibiotics in depth.

• Autism and Non-Antibiotic Properties of Common Beta-lactam Antibiotics

• Macrolide Antibiotics for Some Autism? Or better still, Azithromycin analogue CSY0073, or just Nystatin?

• Antibiotics and Autism(s) – Pass the Bacteroides Fragilis?

and today we covered antivirals.  These are the “anti- drugs” that our reader Tanya referred to as not being useful in her case of autism; I think she will be in the majority.  You have to treat your “minority” case of autism, which is what makes it difficult. 

Almost every common autism treatment strategy is misrepresented as a wonder therapy; that is how you sell books, supplements, lab tests and even now I see expensive "training" courses. The reality is somewhat messy and less convenient, but if you read the science great progress does seem to be possible in many cases.

Acid-sensing Ion Channels (ASICs) and Autism – Acid in the Brain

Acid sensing ion channels (ASICs) are another emerging area of science where much remains known.  It would seem that ASICs have evolved for a good reason, when pH levels fall they trigger a reaction to compensate.  (The lower the pH the higher is the acidity)  In some cases, like seizures, this seems to work, but in other cases the reaction produced actually makes a bad situation worse.

Research is ongoing to find inhibitors of ASICs to treat specific conditions raging from MS (Multiple Sclerosis), Parkinson’s and Huntington’s to depression and anxiety. Perhaps autism should be added to the list.

NSAIDs like ibuprofen are inhibitors of ASICs.

The complicated-looking chart below explains the mechanism.  The ASIC is on the left, also present is a voltage-gated calcium channel (VGCC) and an NMDA receptor. We already know that VGCCs can play a key role in autism and mast cell degranulation. Similarly we know that in autism there is very often either too much or too little NMDA signaling. Here we have all three together.

  

The role of ASICs is to sense reduced levels of extracellular pH (i.e. acidity outside the cell) and result in a response from the neuron. Under increased acidic conditions, a proton (H+) binds to the channel in the extracellular region, activating the ion channel and opening transmembrane domain 2 (TMD2). This results in the influx of sodium ions.

All ASICs are specifically permeable to sodium ions. The only variant is ASIC1a which also has a low permeability to calcium ions. The influx of these cations results in membrane depolarization.

Voltage-gated Ca²⁺ channels are then activated resulting in an influx of calcium into the cell. This causes depolarization of the neuron and an excitatory response released.

NMDA receptors are also activated and this results in more influx of calcium into the cell.

This calcium inflow then triggers further reactions via CaMKII (calmodulin-dependent protein kinase II).

The overall effect is likely to damage the cell.

There is also an important effect on dendritic spines:-

“ASIC2 can affect the function of dendritic spines in two ways, by increasing ASIC1a at synapses and by altering the gating of heteromultimeric ASIC channels. As a result, ASIC2 influences acid-evoked elevations of [Ca²⁺]_i in dendritic spines and modulates the number of synapses. Therefore, ASIC2 may also contribute to pathophysiological states where ASIC1a plays a role, including in mouse models of cerebral ischemia, multiple sclerosis, and seizures”

In general the research is looking to inhibit ASICs to improve a variety of neurological conditions.

Acid in the Brain

ASICs only become activated when there is acidity (low pH).  When the pH is more than 6.9 they do nothing at all.

Unfortunately, in many neurological disorders pH is found to be abnormally low and that includes autism.

ASIC1a channels specifically open in response to pH 5.0-6.9 and contribute to the pathology of ischemic brain injury because their activation causes a small increase in Ca²⁺permeability and an inward flow of Ca²⁺. ASIC1a channels additionally facilitate the activation of voltage-gated Ca2+ channels and NMDA receptor channels upon initial depolarization, contributing to the major increase in intracellular calcium that results in cell death.

However in the case of epilepsy, ASIC1a channels can be helpful.  Seizures cause increased, uncontrolled neuronal activity in the brain that releases large quantities of acidic vesicles. ASIC1a channels open in response and have shown to protect against seizures by reducing their progression. Studies researching this phenomenon have found that deleting the ASIC1a gene resulted in amplified seizure activity. 

Increased brain acidity in psychiatric disorders

Changes in the brain pH level have been considered an artifact, therefore substantial effort has been made to match the tissue pH among study participants and to control the effect of pH on molecular changes in the postmortem brain. However, given that decreased brain pH is a pathophysiological trait of psychiatric disorders, these efforts could have unwittingly obscured the specific pathophysiological signatures that are potentially associated with changes in pH, such as neuronal hyper-excitation and inflammation, both of which have been implicated in the etiology of psychiatric disorders. Therefore, the present study highlighting that decreased brain pH is a shared endophenotype of psychiatric disorders has significant implications on the entire field of studies on the pathophysiology of mental disorders.

This research raises new questions about changes in brain pH. For example, what are the mechanisms through which lactate is increased and pH is decreased? Are specific brain regions responsible for the decrease in pH? Is there functional significance to the decrease in brain pH observed in psychiatric disorders, and if so, is it a cause or result of the onset of the disorder?. Further studies are needed to address these issues.

The following paper is mainly by Japanese researchers and is very thorough; it will likely make you consider brain acidosis as almost inevitable in your case of autism. 

Decreased Brain pH as a Shared Endophenotype of Psychiatric Disorders

Lower pH is a well-replicated finding in the post-mortem brains of patients with schizophrenia and bipolar disorder. Interpretation of the data, however, is controversial as to whether this finding  reflects a primary feature of the diseases or is a result of confounding factors such as medication, post-mortem interval, and agonal state. To date, systematic investigation of brain pH has not been undertaken using animal models, which can be studied without confounds inherent in human studies.  In the present study, we first confirmed that the brains of patients with schizophrenia and bipolar  disorder exhibit lower pH values by conducting a meta-analysis of existing datasets. We then  utilized neurodevelopmental mouse models of psychiatric disorders in order to test the hypothesis  that lower brain pH exists in these brains compared to controls due to the underlying pathophysiology of the disorders. We measured pH, lactate levels, and related metabolite levels in brain homogenates from three mouse models of schizophrenia (Schnurri-2 KO, forebrain-specific  calcineurin KO, and neurogranin KO mice) and one of bipolar disorder (Camk2a HKO mice), and  one of autism spectrum disorders (Chd8 HKO mice). All mice were drug-naïve with the same post-mortem interval and agonal state at death. Upon post-mortem examination, we observed  significantly lower pH and higher lactate levels in the brains of model mice relative to controls. There was a significant negative correlation between pH and lactate levels. These results suggest that lower pH associated with increased lactate levels is a pathophysiology of such diseases rather than mere artefacts.

A number of postmortem studies have indicated that pH is lower in the brains of patients with schizophrenia and bipolar disorder. Lower brain pH has also been observed in patients with ASD. In general, pH balance is considered critical for maintaining optimal health, and low pH has been associated with a number of somatic disorders. Therefore, it is reasonable to assume that lower pH may exert a negative impact on brain function and play a key role in the pathogenesis of various psychiatric disorders.            

Researches have revealed that brain acidosis influences a number of brain functions, such as anxiety, mood, and cognition. Acidosis may affect the structure and function of several types of brain cells, including the electrophysiological functioning of GABAergic  neurons and morphological properties of oligodendrocytes. Alterations in these types of cells have been well-documented in the brains of patients with schizophrenia, bipolar disorder, and ASD and may underlie some of the cognitive deficits associated with these disorders. Deficits in GABAergic neurons and oligodendrocytes have been identified in the mouse models of the disorders, including Shn2 KO mice. Brain acidosis may therefore be associated with deficits in such cell types in schizophrenia, bipolar disorder, and ASD.

Interestingly, we observed that Wnt- and EGF-related pathways, which are highly implicated in somatic and brain cancers, are enriched in the genes whose expressions were altered among the  five mutant mouse strains.

These findings raise the possibility that elevated glycolysis underlies the increased lactate and pyruvate levels in the brains of the mouse models of schizophrenia, bipolar disorder, and ASD.

Dysregulation of the excitation-inhibition balance has been proposed as a candidate cause of schizophrenia, bipolar disorder, and ASD. A shift in the balance towards excitation would result in increased energy expenditure and may lead to increased glycolysis.

UI team develops new way to look at brain function

University of Iowa neuroscientist John Wemmie is interested in the effect of acid in the brain (not that kind of acid!). His studies suggest that increased acidity—or low pH—in the brain is linked to panic disorders, anxiety, and depression. But his work also indicates that changes in acidity are important for normal brain activity too.

“We are interested in the idea that pH might be changing in the functional brain because we’ve been hot on the trail of receptors that are activated by low pH,” says Wemmie, associate professor of psychiatry in the UI Carver College of Medicine. “The presence of these receptors implies the possibility that low pH might be playing a signaling role in normal brain function.”

Wemmie’s previous studies have suggested a role for pH changes in certain psychiatric diseases, including anxiety and depression. With the new method, he and his colleagues hope to explore how pH is involved in these conditions.

“Brain activity is likely different in people with brain disorders such as bipolar or depression, and that might be reflected in this measure,” Wemmie says. “And perhaps most important, at the end of the day: Could this signal be abnormal or perturbed in human psychiatric disease? And if so, might it be a target for manipulation and treatment?”

Panic attacks as a problem of pH

An easy to read article from the Scientific American

Dendritic Spines and ASICS

ASIC2 Subunits Target Acid-Sensing Ion Channels to the Synapse via an Association with PSD-95

The present results and previous studies suggest that ASIC2 can affect the function of dendritic spines in two ways, by increasing ASIC1a at synapses and by altering the gating of heteromultimeric ASIC channels. As a result, ASIC2 influences acid-evoked elevations of [Ca²⁺]_i in dendritic spines and modulates the number of synapses. Therefore, ASIC2 may also contribute to pathophysiological states where ASIC1a plays a role, including in mouse models of cerebral ischemia, multiple sclerosis, and seizures (Xiong et al., 2004; Yermolaieva et al., 2004; Gao et al., 2005; Friese et al., 2007; Ziemann et al., 2008). Interestingly, one previous report suggested increased ASIC2a expression in neurons surviving ischemia, although the functional consequence of those changes are uncertain (Johnson et al., 2001). Moreover, recent studies suggest genetic associations between the ASIC2 locus and multiple sclerosis, autism and mental retardation (Bernardinelli et al., 2007; Girirajan et al., 2007; Stone et al., 2007). Thus, we speculate that ASIC1a and ASIC2, working in concert, may regulate neuronal function in a variety of disease states  

ASICs in neurologic disorders

Disease	Role of ASICs
Parkinson’s disease	Lactic acidosis occurs in the brains of patients with PD.
	Amiloride helps protect against substantia nigra neuronal degeneration, inhibiting apoptosis.
	Parkin gene mutations result in abnormal ASIC currents.
Huntington’s disease	ASIC1 inhibition enhances ubiquitin-proteasome system activity and reduces huntingtin-polyglutamine accumulation.
Pain	ASIC3 is involved in: 1) primary afferent gastrointestinal visceral pain, 2) chemical nociception of the upper gastrointestinal system, and 3) mechanical nociception of the colon.
	Blocking neuronal ASIC1a expression in dorsal root ganglia may confer analgesia.
	NSAIDs inhibit sensory neuronal ASIC expression.
Cerebral ischemia	Neuronal ASIC2 expression in the hypothalamus is upregulated after ischemia.
	Blockade of ASIC1a exerts a neuroprotective effect in a middle cerebral artery occlusion model.
Migraine	Most dural afferent nerves express ASICs.
Multiple sclerosis	ASIC1a is upregulated in oligodendrocytes and in axons of an acute autoimmune encephalomyelitis mouse model, as well as in brain tissue from patients with multiple sclerosis.
	Blockade of ASIC1a may attenuate myelin and neuronal damage in multiple sclerosis.
Seizure	Intraventricular injection of PcTX-1 increases the frequency of tonic-clonic seizures.
	Low-pH stimulation increases ASIC1a inhibitory neuronal currents.
Malignant glioma	ASIC1a is widely expressed in malignant glial cells.
	PcTx1 or ASIC1a knock-down inhibits cell migration and cell-cycle progression in gliomas.
	Amiloride analogue benzamil also produces cell-cycle arrest in glioblastoma.

Source:   Acid-sensing ion channels: potential therapeutic targets for neurologic diseases

One logical question is whether the brain ASIC connection with autism connects to the common  gastrointestinal problems, some of which relate to acidity and are often treated with H2 antihistamines and proton pump inhibitors (PPIs).

Acid-Sensing Ion Channels in Gastrointestinal Function 

Gastric acid is of paramount importance for digestion and protection from pathogens but, at the same time, is a threat to the integrity of the mucosa in the upper gastrointestinal tract and may give rise to pain if inflammation or ulceration ensues. Luminal acidity in the colon is determined by lactate production and microbial transformation of carbohydrates to short chain fatty acids as well as formation of ammonia. The pH in the oesophagus, stomach and intestine is surveyed by a network of acid sensors among which acid-sensing ion channels (ASICs) and acid-sensitive members of transient receptor potential ion channels take a special place. In the gut, ASICs (ASIC1, ASIC2, ASIC3) are primarily expressed by the peripheral axons of vagal and spinal afferent neurons and are responsible for distinct proton-gated currents in these neurons. ASICs survey moderate decreases in extracellular pH and through these properties contribute to a protective blood flow increase in the face of mucosal acid challenge. Importantly, experimental studies provide increasing evidence that ASICs contribute to gastric acid hypersensitivity and pain under conditions of gastritis and peptic ulceration but also participate in colonic hypersensitivity to mechanical stimuli (distension) under conditions of irritation that are not necessarily associated with overt inflammation. These functional implications and their upregulation by inflammatory and non-inflammatory pathologies make ASICs potential targets to manage visceral hypersensitivity and pain associated with functional gastrointestinal disorders.

It looks like it is still early days in the research into ASICs and GI problems. Best look again in decade or two.  

Too Much Lactic Acid – Lactic Acidosis 

One theory is that panic attacks are cause by too much lactic acid.

In earlier posts of mitochondrial disease and OXPHOS, we saw that when the mitochondria have too little oxygen they can continue to produce ATP, but lactate accumulates and this leads to lactic acidosis.

So people with mitochondrial disease might have some degree of lactic acidosis that would reduce extracellular pH and activate ASICs.

So perhaps along with those prone to panic attacks, people with regressive autism and high lactate might benefit from an ASIC inhibitor?

Aerobic exercise is suggested to reduce excess lactate, although extreme exercise like running a marathon will actually make more.  Moderate exercise has the added advantage of stimulating the production of more mitochondria.

So moderate exercise for panic disorders and regressive autism (mitochondrial disease).   Moderate exercise is then an indirect ASIC inhibitor, because it should increase pH (less acidic). 

ASICs in panic and anxiety?

Localization and Behaviors in Null Mice Suggest that ASIC1 and ASIC2 Modulate Responses to Aversive Stimuli 

Acid sensing ion channels (ASICs) generate H⁺-gated Na⁺ currents that contribute to neuronal function and animal behavior. Like ASIC1, ASIC2 subunits are expressed in the brain and multimerize with ASIC1 to influence acid-evoked currents and facilitate ASIC1 localization to dendritic spines. To better understand how ASIC2 contributes to brain function, we localized the protein and tested the behavioral consequences of ASIC2 gene disruption. For comparison, we also localized ASIC1 and studied ASIC1^−/− mice. ASIC2 was prominently expressed in areas of high synaptic density, and with a few exceptions, ASIC1 and ASIC2 localization exhibited substantial overlap. Loss of ASIC1 or ASIC2 decreased freezing behavior in contextual and auditory cue fear conditioning assays, in response to predator odor, and in response to CO₂ inhalation. In addition, loss of ASIC1 or ASIC2 increased activity in a forced swim assay. These data suggest that ASIC2, like ASIC1, plays a key role in determining the defensive response to aversive stimuli. They also raise the question of whether gene variations in both ASIC1 and ASIC2 might affect fear and panic in humans.

Recent genome-wide studies have associated SNPs near ASIC2 with autism (Stone et al., 2007), panic disorder (Gregersen et al., 2012), response to lithium treatment in bipolar disorder (Squassina et al., 2011) and citalopram treatment in depressive disorder (Hunter et al., 2013), and have implicated a copy number variant of ASIC2 with dyslexia (Veerappa et al., 2013). However, little is currently understood about whether ASIC2 is required for normal behavior.

The goals of this study were to better understand the role of ASIC2 in brain function. Thus our first aim was to localize ASIC2 subunits. Because ASIC2 subunits multimerize with ASIC1 subunits, we hypothesized that the distribution of the two subunits would show substantial overlap. In addition, given that ASIC channels in central neurons missing ASIC2 have altered trafficking and biophysical properties, we hypothesized that disrupting expression of ASIC2 would impact behavior. Therefore, we asked if mice missing ASIC2 would have altered behavioral phenotypes, and whether disrupting both ASIC1 and ASIC2 would have the same or greater behavioral effects than disrupting either gene alone. Because we found that ASIC2, like ASIC1, was highly expressed in brain regions that coordinate responses to threatening events, we focused on tests that evaluate defensive behaviors and reactions to stressful and aversive stimuli.

These results suggest that ASIC channels can influence synaptic transmission. We speculate that pH falls to the greatest extent with intense synaptic activity; the mechanism might involve release of the acidic contents of synaptic vesicles, transport of HCO₃⁻ or H⁺ across neuronal or glial cell membranes, and/or metabolism. The reduced pH could activate ASIC channels leading to an increased [Ca²⁺]_i (Xiong et al., 2004; Yermolaieva et al., 2004; Zha et al., 2006). In this scenario, the main function of ASIC channels would be to enhance synaptic transmission in response to intense activity. This would explain the pattern of abnormal behavior in ASIC null mice when the stimulus is very aversive.

Translating ASIC research into therapy

As you may have noticed in the first chart in this post, there already exist ways to inhibit ASICs, ranging from a diuretic called Amiloride to NSAIDs, like ibuprofen.  The process of translating science into medicine has already begun in multiple sclerosis, as you can see in the following study:-

Targeting ASIC1 in primary progressive multiple sclerosis: evidence of neuroprotection with amiloride. 

Our results extend evidence of the contribution of ASIC1 to neurodegeneration in multiple sclerosis and suggest that amiloride may exert neuroprotective effects in patients with progressive multiple sclerosis. This pilot study is the first translational study on neuroprotection targeting ASIC1 and supports future randomized controlled trials measuring neuroprotection with amiloride in patients with multiple sclerosis. 

Agmatine and Spermine

In the graphic at the start of this post you might have noticed Agmatine and Spermine.  While ASICs are acid sensing and so activated by protons, they appear to be also activated by other substances.

The arginine metabolite agmatine may be an endogenous non-proton ligand for ASIC3 channels.

Extracellular spermine contributes significantly to ischemic neuronal injury through enhancing ASIC1a activity. Data suggest new neuroprotective strategies for stroke patients via inhibition of polyamine synthesis and subsequent spermine–ASIC interaction.

However, other research shows spermine promotes autophagy and has been shown to ameliorate ischemia/reperfusion injury  (IRI) and suggests its use in children to prevent IRI .  

So nothing is clear cut.

It looks like spermine, spermidine and agmatine all promote autophagy.            

Agmatine gets converted to a polyamine called putrescene.

Personally, I expect polyamines will generally be found beneficial in autism, but there will always be exceptions.  

Conclusion

There is a case to be made for the use of the diuretic amiloride to treat MS and indeed panic disorders.

Will amiloride help autism? You would not want to use it if there is comorbid epilepsy, since ASICs are “seizure protective”. 

If your genetic testing showed an anomaly with the ASIC2 gene, which is known to occur in both autism and MR/ID, then amiloride would seem a logical therapy.

I think we should not be surprised if people with neurological conditions have lower pH brains than NT people, just like we should expect them to show signs of oxidative stress.

If you do indeed happen to have a rather acidic brain, as seems to be quite often the case, damping down the response from ASICs might make things better or worse, or in indeed a mixture of the two. You would hope, at least in some people, that ASICs provide some beneficial response on sensing low pH.

It would be useful if a researcher did a trial of amiloride in different types of autism, then we might have some useful data. You would think the Japanese researchers would be the ones to do this.

One good thing about amiloride is that it increases the level of potassium in your blood and there even is a combined bumetanide/amiloride pill.  Bumetanide has the side effect of lowering potassium.

Many people with autism find NSAIDs beneficial, either long term or for flare-ups. NSAIDs have many beneficial effects; just how important is ASIC inhibition is an open question.

Is the anxiety that many people with autism seem to suffer, sometimes related to ASICs?  Perhaps it is just a minor panic disorder and it relates to ASIC1 and ASIC2.  I think there are numerous different dysfunctions that produce what we might term “anxiety”, among the long list one day you may well find ASICs.

Science has a long way to go before there is a complete understanding of this subject.

Moderate exercise again appears as a simple therapy with countless biological benefits, in this case reducing lactate and thus reducing acidity (increasing pH).