Friday, 28 November 2014

Is DJ-1 expression negatively associated with severity of Autism? If so, Sodium Benzoate (Cinnamon) may well be beneficial

I do not expect this to be one of my popular posts, but it might deserve to be.

There will be lots of science, but it ends up with a safe potential intervention that can be tried at home.  The good news is that it is inexpensive, tasty and there is already a pretty solid experimental basis for the intervention.

Look in your extended family for relatives with diabetes, COPD (Chronic Obstructive Pulmonary Disease) and Parkinson’s Disease.  This might be useful indicator.

The conclusion is to put some cinnamon in your tea or coffee.

Parkinson’s Disease

Two people recently mentioned Parkinson’s disease to me.

Oxidative stress contributes to the cascade leading to dopamine cell degeneration in Parkinson's disease. This oxidative stress is linked to other components of the degenerative process, such as mitochondrial dysfunction, excitotoxicity, nitric oxide toxicity and inflammation.

The familiar motor symptoms of Parkinson's disease result from the death of dopamine-generating cells in the substantia nigra, a region of the midbrain.

One example of motor symptoms in Parkinson’s can be the inability to walk unaided across a room.  When a series of parallel lines are placed on the floor, the person is then able to cross the room, unaided.  This story was told to me when I explained how Monty, aged 11 with ASD, would sometimes get “stuck” and be unable to leave a room or walk downstairs.  Treatment with Atorvastatin, in Monty, makes these symptoms go away.

It seems that Statins have also been shown to lower the incidence of Parkinson’s.

Statins Protective Against Parkinson's: More Evidence

Further evidence that statin use is associated with a reduction in risk for Parkinson's disease has come from a population study from Taiwan.
The study, published online in Neurology on July 24, was conducted by a team led by Yen-Chieh Lee, MD, Cathay General Hospital, Taipei, Taiwan.
In a large population of statin users, they found a lower risk for Parkinson's in those who continued taking lipophilic statins compared with those who discontinued statins upon having reached their cholesterol goal.
Authors of an accompanying editorial conclude, "For those who have to be on statins, it is a comforting thought that there is a potential added advantage of having a lower risk of PD [Parkinson's disease], and possibly other neurologic disorders as well."

Objective: To evaluate the effect of discontinuing statin therapy on incidence of Parkinson disease (PD) in statin users.
Methods: Participants who were free of PD and initiated statin therapy were recruited between 2001 and 2008. We examined the association between discontinuing use of statins with different lipophilicity and the incidence of PD using the Cox regression model with time-varying statin use.
Results: Among the 43,810 statin initiators, the incidence rate for PD was 1.68 and 3.52 per 1,000,000 person-days for lipophilic and hydrophilic statins, respectively. Continuation of lipophilic statins was associated with a decreased risk of PD (hazard ratio [HR] 0.42 [95% confidence interval 0.27–0.64]) as compared with statin discontinuation, which was not modified by comorbidities or medications. There was no association between hydrophilic statins and occurrence of PD. Among lipophilic statins, a significant association was observed for simvastatin (HR 0.23 [0.07–0.73]) and atorvastatin (HR 0.33 [0.17–0.65]), especially in female users (HR 0.11 [0.02–0.80] for simvastatin; HR 0.24 [0.09–0.64] for atorvastatin). As for atorvastatin users, the beneficial effect was seen in the elderly subgroup (HR 0.42 [0.21–0.87]). However, long-term use of statins, either lipophilic or hydrophilic, was not significantly associated with PD in a dose/duration-response relation.
Conclusions: Continuation of lipophilic statin therapy was associated with a decreased incidence of PD as compared to discontinuation in statin users, especially in subgroups of women and elderly. Long-term follow-up study is needed to clarify the potential beneficial role of lipophilic statins in PD.

Comorbidities, Coincidence and Connections

I am no medical expert, but I am good at noticing connections.

I have already decided that there are some interesting conditions that in some way are connected to autism.  These include:-

·        Diabetes
·        Cancer
·        COPD (Chronic obstructive pulmonary disease)

The connection between Parkinson’s disease and autism are:-

·        Oxidative stress
·        Mitochondrial dysfunction
·        Cognitive and behavioral problems (in late stage Parkinson’s)
·        Motor problems (in early stage and onwards in Parkinson’s and mainly in early stage in Autism)

The motor problems in autism are rarely talked about, but in ABA training programs for young children, teaching fine and gross motor skills plays a major role.  In such children, skills that are automatic in typical children can be totally missing.  You then have to teach very basic skills like controlling a crayon, kicking a ball, catching a ball or stacking wooden blocks.

Later on, motor skills seem to become “normal”.  I am amazed to see how Monty, aged 11 with ASD, can now play the piano with all fingers of both hands racing across the ivory.  A few years ago motor skills were clearly impaired. 

This comes back to autism being a dynamic encephalopathy.  An interesting research finding, I noticed recently, was that while oxidative stress appears life-long in autism, mitochondrial dysfunction appears not to be.  In the samples taken from older people with ASD, mitochondria appeared normal, whereas in young people it was typically abnormal.

It is generally accepted that in most people, autistic symptoms seem to moderate with age.  Either they are getting better at managing themselves, or the dysfunctions themselves are moderating with age.

Parkinson’s is a degenerative disease; in autism only childhood disintegrative disorder seems to be degenerative.

COPD & Parkinson’s

There is a proven connection between COPD (Chronic obstructive pulmonary disease) and Parkinson’s, it is a gene/protein called DJ-1 in COPD, also known as Parkinson disease (autosomal recessive, early onset) 7 or PARK7.

In both conditions DJ-1/PARK7 dysfunction causes a cascade of further events that result in the body losing much of its anti-oxidative defenses.

The protein DJ-1 should act to stabilize NRf2, which is released when there is oxidative stress.  Nrf2 should then activate a large number of anti-oxidant genes that then results in a reaction to the oxidative attack.

The problem is that when DJ-1 is insufficient, Nrf2 never gets as far as activating those anti-oxidant genes and so nothing halts the oxidative attack.

The less DJ-1 expression in a person, the worse their COPD (severe asthma) would be.

As is usually the case in human biology, DJ-1 has numerous other functions.

Note that not only does DJ-1 affect Nrf2, it also is a key negative regulator of PTEN that may be a useful prognostic marker for cancer.

In my earlier post on PTEN and statins we saw that:

Statins up-regulate a known key dysfunctional autism gene, and protein, called PTEN.  I mentioned PTEN in a previous post, since one chemical (Indole-3-carbinol (I3C)) released by eating broccoli also up-regulates PTEN.

From my perspective, upregulating PTEN in autism seems to be helpful.

Parkin, DJ-1, and PINK1 dysfunction in Parkinson’s and Autism

It appears that you need three genetic dysfunctions to develop Parkinson’s disease: parkin, DJ-1, and PINK1. Remarkably very similar dysfunctions seem to exist in autism as well.

As we see in COPD, the DJ-1 dysfunction aggravates the oxidative stress problems.

Note that PINK1, known by its full name, is PTEN-induced putative kinase 1.

The following paper shows how statins affect mitochondria, the role of the Parkinson’s genes and how statins help to clear away the dysfunctional mitochondria that can lead to heart disease.  One can assume that the protective effect of statins against Parkinson’s, must relate to a similar “spring cleaning” of dysfunctional mitochondria, but this time in the brain.

Cells treated with simvastatin also displayed slight mitochondrial depolarization as compared to controls. Induction of autophagy was accompanied by decreases in the pro-growth and proliferation pathways mediated by Akt and mTOR, as well as increases in PTEN. PTEN is linked to mitochondrial quality control via the PTEN-induced putative kinase 1 (PINK1), which recruits the E3 ubiquitin ligase Parkin to mitochondrial membranes in response to depolarization. Parkin, in turn, primes the mitochondria for degradation. Reductions in mitochondria were accompanied by decreasing reactive oxygen species (ROS), which are known to cause oxidative injury and stress. By both depolarizing mitochondria and increasing expression of key autophagic proteins, simvastatin fosters a cellular environment that encourages mitochondrial autophagy (mitophagy), which has been linked to cardioprotection. We therefore propose that these mechanisms underlie the cardioprotective effects of statins that are independent of serum cholesterol levels.

For those wondering what is Mitochondrial Autophagy, read this:-

Mitochondrial Autophagy


Efficient and functional mitochondrial networks are essential for myocardial contraction and cardiomyocyte survival. Mitochondrial autophagy (mitophagy) refers to selective sequestration of mitochondria by autophagosomes, which subsequently deliver them to lysosomes for destruction. This process is essential for myocardial homeostasis and adaptation to stress. Elimination of damaged mitochondria protects against cell death, as well as stimulates mitochondrial biogenesis. Mitophagy is a tightly controlled and highly selective process. It is modulated by mitochondrial fission and fusion proteins, BCL-2 family proteins, and the PINK1/Parkin pathway. Recent studies have provided evidence that miRNAs can regulate mitophagy by controlling the expression of essential proteins involved in the process. Disruption of autophagy leads to rapid accumulation of dysfunctional mitochondria, and diseases associated with impaired autophagy produce severe cardiomyopathies. Thus, autophagy and mitophagy pathways hold promise as new therapeutic targets for clinical cardiac care.

Parkin is a protein which in humans is encoded by the PARK2 gene.

How loss of function of the parkin protein leads to dopaminergic cell death in this disease is unclear. The prevailing hypothesis is that parkin helps degrade one or more proteins toxic to dopaminergic neurons.

PARK2 has now been linked to autism:-

Researchers first fingered PARK2, or parkinson protein 2, in 1998 in five people with Parkinson's disease. The protein has since been shown to help degrade neurons that accumulate in the brains of individuals with the disorder.
PARK2 is an ubiquitin ligase E3, which targets proteins for degradation in the cell. Another protein in the same family, UBE3A, is associated with both autism and Angelman syndrome.
PARK2 is also believed to function in the mitochondria. Several studies have linked mitochondrial dysfunction to autism, suggesting a basis for PARK2's association with the disorder.

This debilitating neurological disorder is caused by mutation of the E3 ubiquitin ligase (Ube3A), a gene whose mutation has also recently been associated with autism spectrum disorders (ASD). However, the function of Ube3A in mediating cognitive impairment in individuals with AS and ASDs, as well as its substrates, have been unknown.
Invention: The Greenberg laboratory first demonstrated that neural activity induces Ube3A transcription, and that a decrease in Ube3A expression decreases the plasma membrane expression of, and synaptic transmission through AMPA glutamate receptors (AMPARs). To better understand the role of Ube3A in AS and ASD, the Greenberg lab identified key neural substrates of Ube3A, Arc and Ephexin5, and the mechanisms for their regulation of synaptic transmission. Their findings suggest mechanisms by which Ube3A contributes to cognitive dysfunction in AS and ASD.
Arc: The Greenberg lab demonstrated that disruption of Ube3A activity leads to an increase of Arc and decrease in AMPAR expression at synapses. Drugs that promote AMPAR expression at synapses, such as metabotropic glutamate receptor subtype 5 (mGluR5) antagonists or compounds that inhibit the expression or function or Arc, may reverse symptoms associated with AS and ASD.
Fragile X is a human disorder in which a similar decrease in AMPAR expression at synapses has been demonstrated. This decrease has further been shown to be a result of excessive mGluR5 signaling, resulting in increased Arc translation and excessive AMPAR internalization. Selective mGluR5 antagonists are now entering clinical trials for the treatment of Fragile X, indicating that this type of therapeutic strategy has potential  

Now to understand what goes wrong in Parkinson's

Parkinson’s disease is the second most prevalent neurodegenerative disorder. Clinically, this disease is characterized by bradykinesia, resting tremors, and rigidity due to loss of dopaminergic neurons within the substania nigra section of the ventral midbrain. In the normal state, release of the neurotransmitter dopamine in the presynaptic neuron results in signaling in the postsynaptic neuron through D1- and D2-type dopamine receptors. D1 receptors signal through G proteins to activate adenylate cyclase, causing cAMP formation and activation of PKA. D2-type receptors block this signaling by inhibiting adenylate cyclase. Parkinson’s disease can occur through both genetic mutation (familial) and exposure to environmental and neurotoxins (sporadic). Recessively inherited loss-of-function mutations in parkin, DJ-1, and PINK1 cause mitochondrial dysfunction and accumulation of reactive oxidative species (ROS), whereas dominantly inherited missense mutations in α-synuclein and LRRK2 may affect protein degradation pathways, leading to protein aggregation and accumulation of Lewy bodies. Mitochondrial dysfunction and protein aggregation in dopaminergic neurons may be responsible for their premature degeneration. Another common feature of the mutations in α-synuclein, parkin, DJ-1, PINK1, and LRRK2 is the impairment in dopamine release and dopaminergic neurotransmission, which may be an early pathogenic precursor prior to death of dopaminergic neurons. Exposure to environmental and neurotoxins can also cause mitochondrial functional impairment and release of ROS, leading to a number of cellular responses including apoptosis and disruption of protein degradation pathways. There is also an inflammatory component to this disease, resulting from activation of microglia that causes the release of inflammatory cytokines and cell stress. This microglia activation causes apoptosis via the JNK pathway and by blocking the Akt signaling pathway via REDD1. 
DJ-1 and Autism

We know that oxidative stress is life-long in many people with autism.  We know that anti-oxidants like NAC (N-acteyl cysteine) and ALA (alpha lipoic acid) improve autism.  It is suggested that ALA in particular may stabilize mitochondrial disease.

ALA also has an interesting effect on glial (dys)function and I am wondering if NAC has the same effect.

Alpha-lipoic acid effects on brainglial functions accompanying double-stranded RNA antiviral and inflammatory signaling.

Viral products in the brain cause glial cell dysfunction, and are a putative etiologic factor in neuropsychiatric disorders, notably schizophrenia, bipolar disorder, Parkinson's, and autism spectrum. Alpha-lipoic acid (LA) has been proposed as a possible therapeutic neuroprotectant.

One of the reasons there is some much oxidative stress in autism may be that those anti-oxidant genes were never activated.  That would happen if DJ-1 expression was low.

The less DJ-1, the more oxidative stress.  This in turn would do many things:-

·        damage the mitochondria
·        damage the DNA
·        upset the homeostasis of the endocrine (hormone) system 
·        disrupt the developing brain (Purkinje cell loss etc)

The end result is a big mess, but amazingly not a degenerative one.

A quick recap on oxidative stress

How to up regulate DJ-1

Thanks to all the research into Parkinson’s, an interesting therapy is available to upregulate DJ-1.  A food additive, Sodium Benzoate, known as E211 or even NaC7H5O2 has been shown to be effective (in mice).

Rather than taking E211 you can eat cinnamon and let your body metabolize it into Sodium Benzoate.  As long as you take the Ceylon type of Cinnamon and not one of the cheaper ones, even very high consumption seems to be risk free.

In the cheaper cinnamon, called Cassia, or Chinese, high levels of a substance called coumarin can be found.  This can be harmful to the kidneys and liver and there are legal limits on this type of cinnamon.


DJ-1 (PARK7) is a neuroprotective protein that protects cells from oxidative stress. Accordingly, loss-of-function DJ-1 mutations have been linked with a familial form of early onset Parkinson disease. Mechanisms by which DJ-1 level could be enriched in the CNS are poorly understood. Recently we have discovered anti-inflammatory activity of sodium benzoate (NaB), a metabolite of cinnamon and a widely-used food additive. Here we delineate that NaB is also capable of increasing the level of DJ-1 in primary mouse and human astrocytes and human neurons highlighting another novel neuroprotective effect of this compound. Reversal of DJ-1-inducing effect of NaB by mevalonate, farnesyl phosphate, but not cholesterol and ubiquinone, suggests that depletion of intermediates, but not end products, of the mevalonate pathway is involved in the induction of DJ-1 by NaB. Accordingly, either an inhibitor of p21ras farnesyl protein transferase (FPTI) or a dominant-negative mutant of p21ras alone was also able to increase the expression of DJ-1 in astrocytes suggesting an involvement of p21ras in DJ-1 expression. However, an inhibitor of geranyl transferase (GGTI) and a dominant-negative mutant of p21rac had no effect on the expression of DJ-1, indicating the specificity of the effect. Similarly lipopolysaccharide (LPS), an activator of small G proteins, also inhibited the expression of DJ-1, and NaB and FPTI, but not GGTI, abrogated LPS-mediated inhibition. Together, these results suggest that NaB upregulates DJ-1 via modulation of mevalonate metabolites and that p21ras, but not p21rac, is involved in the regulation of DJ-1

Cinnamon is well known for its antioxidant potential.  In other research other compounds within it are seen as the active ones.

Here is a very interesting trial showing the effect of cinnamon on lowering cholesterol and blood glucose levels.

This Indian study looked at the effect of 3g a day of cinnamon taken with tea.  Below are the results from the control group, without type II diabetes.

The results are remarkable.  Good cholesterol (HDL) goes up, bad cholesterol (LDL) goes down, tryglicerides go down.  Glucose levels go down.  All the antioxidant indicators go up.

In table 2 in the full report you can see that the effect on people with diabetes was even better.


Colorectal cancer (CRC) is a major cause of tumor-related morbidity and mortality worldwide. Recent research suggests that pharmacological intervention using dietary factors that activate the redox sensitive Nrf2/Keap1-ARE signaling pathway may represent a promising strategy for chemoprevention of human cancer including CRC. In our search for dietary Nrf2 activators with potential chemopreventive activity targeting CRC, we have focused our studies on trans-cinnamic aldehyde (cinnamaldeyde, CA), the key flavor compound in cinnamon essential oil. Here we demonstrate that CA and an ethanolic extract (CE) prepared from Cinnamomum cassia bark, standardized for CA content by GC-MS analysis, display equipotent activity as inducers of Nrf2 transcriptional activity. In human colon cancer cells (HCT116, HT29) and non-immortalized primary fetal colon cells (FHC), CA- and CE-treatment upregulated cellular protein levels of Nrf2 and established Nrf2 targets involved in the antioxidant response including heme oxygenase 1 (HO-1) and γ-glutamylcysteine synthetase (γ-GCS, catalytic subunit). CA- and CE-pretreatment strongly upregulated cellular glutathione levels and protected HCT116 cells against hydrogen peroxide-induced genotoxicity and arsenic-induced oxidative insult. Taken together our data demonstrate that the cinnamon-derived food factor CA is a potent activator of the Nrf2-orchestrated antioxidant response in cultured human epithelial colon cells. CA may therefore represent an underappreciated chemopreventive dietary factor targeting colorectal carcinogenesis.


I think it is fair to say that cinnamon has some very interesting effects in human health, but they are not yet fully understood.

It looks like people with Parkinson’s, COPD, diabetes or high cholesterol could well benefit, for one reason or another.

What is interesting to note is that in some countries the age old herbal remedy for COPD is cinnamon.

I think most people likely would benefit to some extent from cinnamon.  The effective dose is very small, 2 to 4 grams, depending on the study.  

As to the effect in autism, there is only one way to find out.


  1. Just remember that some of us autistics are intolerant to salicylate, and sodium benzoate causes us to have struggles to breathe. So we don't feel good when we drink cooldrinks which contains it.

  2. See ( which reports PTEN depletion in mice causing characteristics of pulmonary hypertension etc. So maybe its the balance between DJ-1 and PTEN and that in 'some of you autists' it's the PTEN that is low. And the same maybe for 'some of us COPDs' as cinnamon doesn't seemed to have helped me.

    1. Very interesting. PTEN is low in some people with autism. Statins and PPAR gamma can be used to increase PTEN. Both improve autism

      Regulation of the PTEN promoter by statins and SREBP

      It is worth considering sulfurophane if you have COPD. In this blog you will see that this can be achieved with broccoli sprout powder, as long as it has the active enzymes preserved. There is now a COPD trial using sulfurophane at Johns Hopkins.

  3. Thanks. Yes I have had a little go with the 'good' sulfurophane , investigating that is how I found your site.

    My problem is that I am one of the 30% COPD people who have only limited symptoms so that its not relief from them that I want, its a cure. Hence my interest in upregulating DJ-1 because Peter Barnes mentioned it was in part also involved in repair, renovation - although according to everyone it's a futile hope in the case of COPD.

    By the way have you come accross Yamoa tree bark extract? It's supposed to modulate the immune system by effecting the beta gamma T cells and restoring the T1 T2 balance by reducing the T2 response and upping the T1 response which explains why it works well for asthma. (Of course COPD is a T1 excessive response, just my luck.) Who knows, maybe it could have an impact on autism too and be a component of your polypill? See

    1. Thanks for the link.

      You might just have to try many epigenetic therapies until you get lucky.

      What about the low dose Theophylline, which at sub-therapeutic does do this?

    2. In a recent publication ( ) Duan et al report that NFκB signaling is a positive regulator for PINK1 gene expression so that lipopolysaccharide (LPS), which is a strong activator of NFκB, had the same effect. Lipopolysaccharides are found in the outer membrane of Gram-negative bacteria, and elicit strong immune responses in animals (Wiki). But Graff et al ( found that 'Gene expression patterns in purified bovine γδ T cells and monocytes induced by Yamoa™ were similar to those induced by ultrapure lipopolysaccharide' and much more potent in human γδ T cells.

      Does this mean that Yamoa extract also will upregulate PTEN/PINK1?

    3. I do not know if Yamoa extract also will upregulate PTEN/PINK1,
      but I do know that statin drugs upregulate PTEN

      but if PTEN is increased too far, you risk causing type 2 diabetes.


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