Showing posts with label PINK1. Show all posts
Showing posts with label PINK1. Show all posts

Monday, 8 June 2015

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

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

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

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

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

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

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


Autophagy is a very complex process.

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

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

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

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

Autophagy and cell death

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

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

Autophagy mainly maintains a balance between manufacture of cellular components and break down of damaged or unnecessary organelles and other cellular constituents.
There are some major degradative pathways that include proteasome that involves breaking down of most short-lived proteins.

Autophagy and stress

Autophagy enables cells to survive stress from the external environment like nutrient deprivation and also allows them to withstand internal stresses like accumulation of damaged organelles and pathogen or infective organism invasion.
Autophagy is seen in all eukaryotic systems including fungi, plants, slime mold, nematodes, fruit flies and insects, rodents (laboratory mice and rats), humans.

Types of autophagy

There are several types of Autophagy. These are:-

·         microautophagy – in this process the cytosolic components are directly taken up by the lysosome itself through the lysosomal membrane.
·         macroautophagy – this involves delivery of cytoplasmic cargo to the lysosome through the intermediary of a double membrane-bound vesicle. This is called an autophagosome that fuses with the lysosome to form an autolysosome.
·         Chaperone-mediated autophagy – in this process the targeted proteins are translocated across the lysosomal membrane in a complex with chaperone proteins (such as Hsc-70).  
·         micro- and macropexophagy
·         piecemeal microautophagy of the nucleus
·         cytoplasm-to-vacuole targeting (Cvt) pathway

Autophagy & Autism

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

Verapamil, Autophagy and Calpains

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

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

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

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

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

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

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

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


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

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

Mitophagy & PINK1

Mitophagy is a necessary ongoing “spring cleaning” of damaged bits of mitochondria.
It appears that in some autism, this process goes awry and damaged mitochondria accumulate.

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

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

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

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

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

Obesity & Autism

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

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

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


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

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

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

 ·        Mitochondrial dysfunction

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

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

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.