Yet more money was just donated to autism research. In 2017 the CEO of Broadcom gave $20 million to MIT and now he has given $20 million to Harvard, where he did his MBA.
Time to boost Homer's mitochondria?
I think philanthropists from the fast-moving IT sector should demand rather more from the slow-moving world of autism research. I also think common sense is often more lacking than money.
The US Government has also just announced $1.8 billion for autism research.
Donald Trump authorized a five-year extension of the Autism Collaboration, Accountability, Research, Education and Support (CARES) Act. The 2014 act dedicated funds to children with autism spectrum disorder, but the new version includes adults. Children with autism do indeed grow up to become adults with autism.
Today we look at further applications of DMF, which is a cheap chemical also sold as a very expensive drug.
We learnt from Dr Kelley, from Johns Hopkins, that most regressive autism features mitochondrial dysfunction. Mitochondria within cells produce ATP (fuel) via a complex multi-step process called OXPHOS. If you lack any of the required enzyme complexes for OXPHOS, that part of your body will suffer a power shortage/outage. Another potential problem is just too few mitochondria.
The treatment for mitochondrial disease is mainly to avoid further damage, using antioxidants. If you know which enzyme complex is lacking, you might try and target that.
Among other interactions, PGC-1α is affected by something called PPAR-γ (Peroxisome proliferator-activated receptor gamma), also known as the glitazone receptor.
There are many cheap drugs that target PPAR-γ, because this is also one way to treat type 2 diabetes. We saw that Glitazone drugs have been successfully trialed in autism.
Today we look at another way to activate PGC-1α and stimulate the production of more mitochondria and increase the necessary enzyme complexes for OXPHOS.
Many people with autism in the US are diagnosed by their MAPS/DAN doctor as lacking Complex 1.
DMF has two principal effects. It affects NRF2 and HCAR2.
Many supplements sold online are supposed to activate NRF2, but may well lack potency.
Activating NRF2 turns on your antioxidant defences and so is good for people with autism, diabetes, COPD and many other conditions, but is bad for someone with cancer.
We will see later how, somewhat bizarrely, at high doses DMF reverses function and causes cell death via oxidative stress, making it a potent potential cancer therapy. Cancer cells are highly vulnerable to oxidative stress.
In this blog we are focusing on low doses of DMF, that are NRF2 activating.
In the chart below the NFE2L2 gene encodes the transcription factor NRF2. We want the antioxidant genes turned on.
We then get another benefit because NRF2 expression also regulates NRF1 expression.
The transcription factor NRF1 is another regulator of mitochondrial biogenesis with involvements in mitochondrial replication and transcription of mitochondrial DNA.
We then get a third benefit from DMF via activating HCAR2, this time we increase Complex I expression. In the OXPOS multistep process to make fuel/ATP the bottleneck is usually Complex I, so Complex I is often referred to as being “rate limiting”. Complex I is the most important deficiency to fix.
Dimethyl fumarate mediates Nrf2-dependent mitochondrial biogenesis in mice and humans
The induction of mitochondrial biogenesis could potentially alleviate mitochondrial and muscle disease. We show here that dimethyl fumarate (DMF) dose-dependently induces mitochondrial biogenesis and function dosed to cells in vitro, and also dosed in vivo to mice and humans. The induction of mitochondrial gene expression is more dependent on DMF's target Nrf2 than hydroxycarboxylic acid receptor 2 (HCAR2). Thus, DMF induces mitochondrial biogenesis primarily through its action on Nrf2, and is the first drug demonstrated to increase mitochondrial biogenesis with in vivo human dosing. This is the first demonstration that mitochondrial biogenesis is deficient in Multiple Sclerosis patients, which could have implications for MS pathophysiology and therapy. The observation that DMF stimulates mitochondrial biogenesis, gene expression and function suggests that it could be considered for mitochondrial disease therapy and/or therapy in muscle disease in which mitochondrial function is important.
DMF for Friedreich's ataxia
Friedreich's ataxia (FA) is a genetic disease caused by mutations in the FXN gene on the chromosome 9, which produces a protein called frataxin. It causes difficulty walking, a loss of sensation in the arms and legs and impaired speech that worsens over time. Symptoms typically start between 5 and 15 years of age. Most young people diagnosed with FA require a mobility aid such as a wheelchair by their teens. As the disease progresses, people lose their sight and hearing. Other complications include scoliosis and diabetes.
Frataxin is required for the normal functioning of mitochondria, the energy-producing factories of cells. Mutations in the FXN gene lead to a decrease in the production of frataxin and the consequent disruption in mitochondrial function.
No effective treatment exists. FA shortens life expectancy due to heart disease, but some people can live into their sixties.
Friedreich’s Ataxia (FA) is an inherited neurodegenerative disorder resulting from decreased expression of the mitochondrial protein frataxin, for which there is no approved therapy. High throughput screening of clinically used drugs identified Dimethyl fumarate (DMF) as protective in FA patient cells. Here we demonstrate that DMF significantly increases frataxin gene (FXN) expression in FA cell model, FA mouse model and in DMF treated humans. DMF also rescues mitochondrial biogenesis deficiency in FA-patient derived cell model. We further examined the mechanism of DMF's frataxin induction in FA patient cells. It has been shown that transcription-inhibitory R-loops form at GAA expansion mutations, thus decreasing FXN expression. In FA patient cells, we demonstrate that DMF significantly increases transcription initiation. As a potential consequence, we observe significant reduction in both R-loop formation and transcriptional pausing thereby significantly increasing FXN expression. Lastly, DMF dosed Multiple Sclerosis (MS) patients showed significant increase in FXN expression by ~85%. Since inherited deficiency in FXN is the primary cause of FA, and DMF is demonstrated to increase FXN expression in humans, DMF could be considered for Friedreich's therapy.
High Dose DMF to treat some cancer
Some readers may recall that the protein DJ-1 is encoded by the Parkinson’s gene PARK7 and that DMF has already been proposed as a therapy for Parkinson’s disease.
At high doses of DMF the protein DJ-1 loses its stabilization function and ends up effectively blocking NRF2. Put simply, high dose DMF turns off NRF2, making it a cancer cell killer.
Dimethyl Fumarate Controls the NRF2/DJ-1Axis in Cancer Cells: Therapeutic Applications
The transcription factor NRF2 (NFE2L2), regulates important antioxidant and cytoprotective genes. It enhances cancer cell proliferation and promotes chemoresistance in several cancers. Dimethyl fumarate (DMF) is known to promote NRF2 activity in noncancer models. We combined in vitro and in vivo methods to examine the effect of DMF on cancer cell death and the activation of the NRF2 antioxidant pathway. We demonstrated that at lower concentrations (<25 a="" activation="" antioxidant="" cytoprotective="" dmf="" has="" mol="" nrf2="" of="" pathway.="" role="" span="" the="" through=""> At higher concentrations, however (>25 μmol/L), DMF caused oxidative stress and subsequently cytotoxicity in several cancer cell lines. High DMF concentration decreases nuclear translocation of NRF2 and production of its downstream targets. The pro-oxidative and cytotoxic effects of high concentration of DMF were abrogated by overexpression of NRF2 in OVCAR3 cells, suggesting that DMF cytotoxicity is dependent of NRF2 depletion. High concentrations of DMF decreased the expression of DJ-1, a NRF2 protein stabilizer. Using DJ-1 siRNA and expression vector, we observed that the expression level of DJ-1 controls NRF2 activation, antioxidant defenses, and cell death in OVCAR3 cells. Finally, antitumoral effect of daily DMF (20 mg/kg) was also observed in vivo in two mice models of colon cancer. Taken together, these findings implicate the effect of DJ-1 on NRF2 in cancer development and identify DMF as a dose-dependent modulator of both NRF2 and DJ-1, which may be useful in exploiting the therapeutic potential of these endogenous antioxidants.
Proposed mechanism of DMF-induced cancer cell death. Low concentrations of DMF can induce the NRF2 antioxidant pathway, allowing NRF2 nuclear translocation and binding to the antioxidant response elements leading to the transcription of antioxidant and detoxifying enzymes, thereby promoting cell survival. High concentrations of DMF, however, induce disruption of the NRF2 stabilizer DJ-1, which in turn impairs NRF2 induction and transcriptional activities in response to DMF, induces ROS generation, GSH depletion, and hence, facilitates cancer cell death. Cys, cysteine; 2SC, succination of cysteine residues.
Conclusion
This post did not cost $20 million, it is yours for free.
It looks pretty obvious that people with autism caused by, or associated with, mitochondrial dysfunction might potentially benefit from DMF.
People with Friedreich’s Ataxia do not currently have any treatment options. Low dose DMF is free of side effects, the high doses used to treat Psoriasis and Multiple Sclerosis often cause troubling GI side effects.
DMF seems to have very many potential therapeutic applications, limited only by the cost of the pharmaceutical version of this cheap chemical. Fortunately the "autism dose" is tiny.
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