Background: The lipid soluble or fatty nature of toxicity has led us to seize the complexity of neurological presentations by addressing them from a cell membrane perspective. Examination of red cell lipids shows many chemicals, pesticides, biotoxins (from mold) and heavy metals in subjects with Motor Neuron Disease, Autism, Multiple Sclerosis, Post Stroke, Epilepsy, Alzheimer’s and Parkinson’s Disease. Thousands of analyses has revealed a characteristic accumulation of very long chain fatty acids (VLCFAs), which comprise lipid rafts, or ceramides, and can cause cell membrane derangement as well as poor cell signaling. Basically the cell membrane is so important that the accumulation of all these biotoxins, chemicals and heavy metals stored through these VLCFA’s cause significant dysfunction in the cells of the body but particularly in the brain.
Membrane phospholipid abnormalities with elevation of VLCFAs may be indicative of exposure to fat soluble neurotoxins resulting in suppressed (peroxisomal beta oxidation of VLCFAs) or ability to create energy from fatty acids. Also many individuals have disturbances in methylation due to toxic exposure. This may further destabilize the membrane phospholipid structure (cell membrane) and alter DNA expression / Gene expression due to deficits in the enzymes Methylene Tetrahydrofolate Reductase (MTHFR) and Methionine Synthase. In other words toxic build up happens in the cell membranes and causes lots of problems. It is important to “turn over your cell membranes” which can be done through the specific program we have developed.
The use of oral and IV lipids may facilitate stabilization of phospholipids in cell membranes thereby addressing cell membrane integrity. The addition of intravenous phenylbutrate addresses neuroinflamation by increasing the beta oxidation of VLCFAs. See how Phenylbutrate is being studied for treatment for Parkinson’s Disease.
In order to detoxify the accumulation of toxins and stabilize cell membrane function, we have embarked on a clinical protocol to address the accumulation of aberrant lipids and ceramides with oral and IV phenylbutyrate, phosphatidylcholine, methylation factors (folinic acid, riboflavin, methylcobalamin) and Glutathione.
The administration of Phosphatidylcholine, Phenylbutyrate, Methylation Support and Glutathione may offer a new therapeutic strategy for neurological disorders involving neurotoxic exposure, a significant cause of Parkinson’s disease!
“Listen to your gut” is common advice when faced with an important decision. Researchers are now heeding these words to gain further insights into Parkinson’s disease (PD).
The human digestive tract contains up to a thousand different types of bacteria, which help you digest food, make vitamins and maintain your immune system. The amount of bacteria is influenced by diet, age and other variables, and is thus unique to each individual.
Filip Scheperjans, MD, PhD, and colleagues from the University of Helsinki, Finland examined the intestinal contents of 72 people with Parkinson’s and 72 without PD. Their research, funded by MJFF and published recently in Movement Disorders, revealed that people with Parkinson’s had lower levels of a certain bacterium and that concentrations of another bacterium varied among subgroups of those with PD with differing motor symptoms.
Intestines as a Window to the Brain There is a clear effect of Parkinson’s disease on the gastrointestinal system. Nearly 80 percent of people with PD have constipation, and this condition often predates the motor symptoms of Parkinson’s by several years.
Additionally, alpha-synuclein — a protein that clumps in the brains of all people with Parkinson’s — has been found in several locations outside the brain, including the nerves controlling the intestines. Investigators question whether the abnormal protein could show up here first, causing non-motor symptoms, and later spread to the brain to cause motor symptoms.
Lastly, researchers believe the normal bacteria of the gut might affect the functioning of the gut nerves which could in turn affect the nerves of the brain.
Specific Bacterial Levels Are Affected in Parkinson’s Disease
In Dr. Scheperjans’ study, the bacteria Prevotella was present at lower levels in the guts of people with Parkinson’s disease. This bacterium aids in the creation of the vitamins thiamine and folate and the maintenance of an intestinal barrier protecting against environmental toxins. This finding may therefore have implications not only for diagnosis but also for dietary adjustments or vitamin supplementation for management of PD in the future.
In people with Parkinson’s with more severe postural instability and gait difficulty, as opposed to tremor, the bacterium Enterobacteria was present at higher levels. The reasons for this association were not clear.
Studying Intestinal Bacteria Will Advance Understanding of Parkinson’s Deciphering information from the gut could lead to earlier and more definitive diagnosis, a better understanding of how Parkinson’s progresses, and ways to separate the populations of people with differing symptoms of PD.
If researchers determine that there are specific and consistent differences in the gut, bacteria may serve as biomarkers — objective measurements to diagnose or track PD. As the gut is much more accessible than the brain and can be analyzed through stool samples, a bacterial biomarker is an attractive prospect.
Additionally, we don’t know why people with Parkinson’s disease show such varied motor symptoms (gait problems versus tremor, for example) or who will get which. Bacterial differences may allow us to separate the subtypes of Parkinson’s and, as a result, give individuals a better idea of the symptoms and disease progression they might expect.
More Research Is Needed
Further studies are called for to learn more about the relationship between these and other gut bacteria and Parkinson’s. In the meantime, researchers are intensely studying alpha-synuclein to determine how and why this protein contributes to Parkinson’s, and its connection between the gut and the brain.
Until a disease-modifying therapy is found, symptomatic treatments, including a drug for constipation, remain under development.
Comment:
Interesting that they end this editorial with a plug for a drug. Seems like there is a pill for every ill in the USA. Currently I’m traveling Europe and studying with doctors treating Parkinsons Disease in countries like Germany and Switzerland and to my amazement I am seeing a much more holistic environment at the pharmacies and with the approaches of many of the physicians here compared to our “bought and paid for pharmaceutical health care model in the good ‘ol USA”. Well back to this article I would have to say what comes first the chicken or the egg? IS the constipation many PD patients have the cause of the alpha synicien build up in the brain or is it a future complication that accelerates the disease later in the process? Well either way it is important to address this but I feel a more holistic approach is better such as activation the area of the brain that drives autonomic function that would improve gut movement as well as natural supplements that would promote better gut function. I personally like homozon for this and functional neurology for the activation part. See FunctionalCranialRelease.com for more on that.
Recent articles in the New England Journal of Medicine indicate that a person may have iron overload without having a hereditary disease called hemochomatosis or other obvious reasons for the problem such as multiple blood transfusions or other obvious exposure. Another study of heart disease, 13% of those screened had indicators of iron overload. This cannot be explained by heredity. It also correlates with findings in my own practice and other physicians using nutritional functional medicine.
Why is this important to someone who has a diagnosis of Parkinson’s? Well lets first look at what Iron does in the body.
Iron has three major roles in the body:
1. It transport oxygen to the cells through hemoglobin.
2. Iron is needed for energy production in every cell through ATP production.
3. Iron assists in catalase Production. Catalase is an enzyme that travels around the body and picks up free oxygen atoms called free radicals.
Several reports have suggested that iron accumulation in Parkinson’s patients might contribute to oxidative stress during Parkinson’s Disease.
Nigral Iron Elevation Is an Invariable Feature of Parkinson’s Disease and Is a Sufficient Cause of Neurodegeneration!
Is iron elevation contributing to neuronal death in Parkinson’s disease, or is it simply a feature of dying neurons? YES! Examples demonstrate that a primary elevation in nigral iron is a sufficient cause of Parkinsonian neurodegeneration; thus iron elevation evidenced in familial and sporadic cases of PD has the clear potential to contribute to the degenerative process. A variety of animal models have demonstrated that iron elevation is sufficient to cause neurodegeneration in the nigra. Direct injection of iron into the midbrain region of rats causes SN neuronal loss. A number of studies employing an iron feeding protocol to neonatal mice have shown Parkinsonism and nigral degeneration in these mice when they reach adulthood.
Iron elevation can cause oxidative stress-mediated cell death. Within biological systems iron can react with oxygen to catalyze the formation of the toxic hydroxyl radical via the Fenton reaction. This leads to the accumulation of alpha synuclein deposition and Parkinson’s Lewy body pathology! Alpha synuclein is often considered the Parkinson’s protein owning to extensive links to the disease. Aggregated alpha synuclein is also the major component of Lewy bodies, the pathological hallmark for PD. Alpha synuclein binds to iron, which accelerates its aggregation into fibrils. Alpha synuclein has also been shown to directly generate hydrogen peroxide when it aggregates and, in the presence of iron, produce toxic hydroxyl radicals. Iron is also found enriched in Lewy bodies, providing in vivo evidence that iron elevation could induce Lewy body deposition in PD.
So is iron elevation the cause of PD? Not really, since there has to be some other process that causes iron to elevate in the first place. The same could be said of any other factor implicated in PD. If alpha synuclein is the cause of Parkinson’s disease, what causes the protein to aggregate? Understanding the cause of PD may be difficult to define.
Oxidative damage via Glutathione depletion might also accelerate the build-up of defective proteins leading to cell death of Substatia Nigra neurons by impairing anti oxidant activity. Replenishment of normal glutathione levels within the brain may hold an important key to therapeutics for PD. Is the Glutathione assisting the brain to deal with a high level of iron? Is the iron depleting the Glutathione because there is a higher need to quench the increased level of oxidative stress in the brain? I would suggest yes! I have seen many patients in my Functional Neurological practice who I have placed on GlutaMax which is a Glutathione suppository or GlutaGenisis, a nebulized form of Glutathione and seen positive subjective and objective findings clinically. I like the suppository form because there is a slow release with peak plasma levels (levels in your blood) 5-6 hours long! It should be noted that Glutathione will not absorb well through the gut so forget about oral Glutathione. Looking at Iron toxicity and working with PD patients to clear this heavy metal from the body and brain may hold great clinical benefit along with supplementing with Glutathione!
IRON IN THE AVERAGE DIET
There is some evidence that the average American diet includes excess iron for men but perhaps not enough for menstruating women. I tend to disagree with this, as many women today have iron toxicity to some degree, as revealed on hair mineral analyses.
Higher iron foods include liver, kidneys, all red meats, chicken, turkey, eggs, clams, oysters, other seafood, many fish, kelp, blackstrap molasses, brewer’s and torula yeast, bone meal, sunflower and pumpkin seeds, dark green vegetables, and soybeans. Iron is also added to most white flour products, and it is found in some vitamin pills and other vitamin/mineral preparations.
EXCESSIVE SOURCES OF IRON
1. White Flour Products. The most important single source of excess iron is refined wheat flour products.
2. Vitamin Supplements And Tonics With Iron.
3. Red Meat And, To A Limited Degree, All Dark-colored Foods.
4.Tobacco can be high in iron depending on the soil on which it is grown. Alcohol intake of any amount tends to worsen iron overload difficulties because alcohol depletes zinc, an important iron antagonist.
6. Pollution. Iron contamination of the air, water and soil is quite common, especially in iron-producing areas of the nation such as the Midwestern US and parts of California, Arizona and others as well. Industrial iron contamination may also occur anywhere. Water supplies, especially if the water is slightly yellow or orange, are a common source of excess inorganic iron. Wells should always be tested for iron contamination. Iron cookware is a source of iron if used to cook tomatoes or other acidic foods. Rarely is this a major problem, however, if the other sources are not in the picture.
7. Occupational Exposure. Welders, electrical workers who use solder, iron and pipe workers, steel fabricators and other occupations may expose one to enormous quantities of toxic iron.
8. Emotional Iron Sources. Holding on to one’s anger or rage appears to keep iron in the body. While this is not a source of iron toxicity, it still has an extremely damaging effect. In fact, anger, rage, and hostility, all traits associated with iron, are qualities associated with planet earth, which is an iron-rich planet.
IRON AND HAIR TISSUE MINERAL ANALYSIS MIGHT BE THE BEST TEST TO DETERMINE OVERLOAD!
Hair tissue mineral analysis is helpful to identify an iron imbalance in most cases, but one must not just use the hair iron level. Here are the main indicators:
1. HAIR TISSUE IRON GREATER THAN ABOUT 2 MG%. this indicator applies mainly to an initial hair mineral test before any treatments the hair iron may elevate as the body eliminates excess iron through the hair.
2. IRON IN THE LOW RANGE. This is a hair tissue iron level of less than about 1.2 mg%. It indicates the body is having difficulty clearing iron.
3. ELEVATED MANGANESE OR ALUMINUM. When aluminum is above about 1.2 mg% or manganese is greater than about 0.04 mg% in the hair tissue, iron toxicity with biounavailable iron is almost always present.
Whys to clear out Iron from the body and brain.
Iron is difficult for the human body to eliminate. This may be because iron is such an essential mineral. The body conserves iron carefully, rather than risk excreting too much. Humans often had to survive on low-iron vegetable diets for months, so iron conservation was essential. Today we have the opposite situation in many parts of the world. White flour in enormous amounts, along with red meat and iron-rich vegetables are in abundance in most developed nations. Also, excessive iron in the air and water supplies are common. The only methods I am aware of to remove excess iron from the body are:
1. Avoiding Dietary Iron.
2. Decreasing the body’s need for Iron.
2. Phlebotomy or bleeding (removing blood).
3. Iron chelating drugs and other substances.
Diet. Iron toxicity is often largely caused by dietary imbalances. The diet must exclude white flour and some red meat except perhaps lamb once or twice a week. Other restrictions for iron are usually not needed, except perhaps to avoid molasses, red beets or other very high-iron foods or using a lot of iron cookware. Eliminate all sugars, including most all fruit, all fruit juices, which upset blood sugar, and all other sweet foods.
More Rest, Emotional Adjustment, if needed, And A Healthful, Low-Stress Lifestyle. Rest, stress reduction and releasing negative emotions are essential for the best results.
Emotions such as anger, rage and resentment greatly increases iron retention in some individuals. The body seeks to maintain adequate adrenal activity by retaining iron and manganese, among other minerals. These, in fact, can irritate weak adrenal glands, which keeps the adrenals pumping out hormones when they would prefer rest.Reduce The Activity Of The Sympathetic Nervous System. The sympathetic nervous system inhibits proper digestion, proper elimination and many other vital body functions. It is a fight-or-flight response that millions of people are caught in. Assist the Eliminative Organs. Any method that assists the liver, kidneys, bowels and skin will help remove iron, as well as all other toxic substances in the body. Many methods are available to do this. Infrared saunas, coffee enemas, and, at times, herbs such as milk thistle, black radish, dandelion or uva ursi to assist the activity of the colon, kidneys and liver, primarily. The right amount of iron antagonists minerals such as manganese, chromium, selenium and zinc should be taken.
Iron clearing or chelators.
One of my personal favorites is Lactoferrin.
Lactoferrin up-regulates the immune system by regulating iron in the body, with the Apolactoferrin form functioning specifically to lower iron levels.
Green tea can absorb iron and prevent the absorption of iron.
One can drink green tea with each meal and also take green tea extract supplements which may be more effective. You would want to take the extract that contains concentrated polyphenols and tannins. Four to ten capsules daily are needed, each with a polyphenol content of about 300 mg at least, according to Disease Prevention And Treatment.
Another chelator is vitamin C, except for the somewhat serious difficulty that vitamin C also enhances iron absorption, so is less useful unless given intravenously.
MEDICAL METHODS FOR REMOVING IRON
1. Bloodletting. Leeches or phlebotomy (removing blood by intravenous needle) have been and are presently the major methods used to reduce iron levels in cases of disorders involving excessive iron.
2. Chelating Drugs. Iron chelators such as deferoxamie, penecillamine or even EDTA to some degree will remove some iron. Deferiprone, was recently shown to benefit PD patients in a phase II clinical trial (PMID: 24251381) [113]. This is the first drug to show a disease-modifying effect for PD, which highlights the potential for targeting iron for PD pharmacotherapy, and strongly implicates iron in the disease mechanism. This method is not used much as it is not safe, the drugs can be toxic, and it is more costly as well. I think they need to do a study using more natural methods to remove iron and publish that!
Problems with iron chelators include:
a) Other vital minerals and other substances may be removed
b) Deferoxamine and other drugs are toxic to a degree.
c) They remove both available and biounavailable iron, which is not good at all.
d) They do not tend to address the underlying causes. Chelation may address some causes if it is able to remove lead, cadmium and other toxic metals. However, chelation can also worsen mineral imbalances in some people, especially those with low tissue calcium or magnesium or zinc levels.
In conclusion I highly recommend anyone who is dealing with a Parkinson’s Diagnosis begin to explore iron as a possible issue in the matrix of issues seen in the disease. I work with patients all over the world who have Parkinson’s and would be available for consultation!
Tianma (Gastrodia elata Blume) is a traditional Chinese medicine (TCM) often used for the treatment of headache, convulsions, hypertension and neurodegenerative diseases. Tianma also modulates the cleavage of the amyloid precursor protein App and cognitive functions in mice. The neuronal actions of tianma thus led us to investigate its specific effects on neuronal signalling. Accordingly, this pilot study was designed to examine the effects of tianma on the proteome metabolism in differentiated mouse neuronal N2a cells using an iTRAQ (isobaric tags for relative and absolute quantitation)-based proteomics research approach. We identified 2178 proteins, out of which 74 were found to be altered upon tianma treatment in differentiated mouse neuronal N2a cells. Based on the observed data obtained, we hypothesize that tianma could promote neuro-regenerative processes by inhibiting stress-related proteins and mobilizing neuroprotective genes such as Nxn, Dbnl, Mobkl3, Clic4, Mki67 and Bax with various regenerative modalities and capacities related to neuro-synaptic plasticity.
Discussion
Orchids and their derivatives have been used for many years in clinical studies to treat various neuronal disorders and demonstrated a powerful effect [4,6]. In our previous study, we could demonstrate the effect of tianma on cognitive functions in mice [12]. Here, we provide an additional interesting insight into the molecular and cellular mechanisms of herbal medicine by disclosing the effect of tianma on the full neuronal proteome changes upon stimulation of differentiated mouse neuronal N2a cells. In the following sections we briefly discuss the identified proteins that were found to be altered upon neuronal tianma stimulation and we hypothesize potential applications of tianma that may emerge from our data obtained:
Increased neuro-protective protein levels in differentiated neuronal N2a cells upon tianma activation
Nxn: Nucleoredoxin is a novel thioredoxin family member that is involved in cell growth and differentiation where it sustains Wnt/β-catenin signalling by retaining a pool of inactive dishevelled protein [27-29]. Its activation by tianma allows the herb to influence pivotal neuronal differentiation pathways. In fact, we observed slightly enhanced neurite extension formation after adding tianma to the neuronal cells (Figure 2C).
Dbnl: Similarly, tianma partakes in cell differentiation processes by mobilizing Dbnl [30]. Dbnl deficiency leads to tissue and behavioral abnormalities and impaired vesicle transport [31]. It is a cytoskeletal protein that may serve as a signal-responsive link between the dynamic cortical actin cytoskeleton and regions of membrane dynamics such as neurite-outgrowth processes and synaptic plasticity [32].
Mobkl3: Mobkl3 is both a member and a putative substrate of striatin family-protein phosphatase 2A (PP2A) complexes [33], an enzyme that belongs to a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling [34] which has been shown to participate in various signalling events crucially involved in neurodegenerative processes [35,36]. This adds a further interesting aspect on tianma’s potential application for a possible treatment of neurological diseases [4,12].
Clic4: Clic4 (chloride intracellular channel 4) is a multifunctional protein that localizes to the mt and cytoplasm and also traffics between the cytoplasm and nucleus while it interacts with Schnurri-2, a transcription factor in the bone morphogenetic protein (BMP) signalling pathway. Transforming growth factor beta (TGF-beta) promotes the expression of Clic4 and Schnurri-2 as well as their association in the cytoplasm and their translocation to the nucleus. In the absence of Clic4 or Schnurri-2, TGF-beta signalling is abrogated. Direct nuclear targeting of Clic4 enhances TGF-beta signalling and removes the requirement for Schnurri-2. Nuclear Clic4 associates with phospho (p)-Smad2 and p-Smad3, protecting them from dephosphorylation by nuclear phosphatases. These result in newly identified Clic4 as modifier of TGF-beta signalling through its function as stabilizer of p-Smad2 and 3 in the nucleus which is essential for Clic4-mediated growth-arrest and differentiation [37]. In addition, Clic4 mediates TGF-beta1-induced fibroblast-to-myofibroblast transdifferentiation [38] and is required for Ca2+-induced keratinocyte differentiation [39]. Proteomic analysis of vascular endothelial growth factor-induced endothelial cell differentiation reveals a role for Clic4 in tubular morphogenesis also hinting at its involvement in neuronal differentiation processes [40]. Furthermore, Clic4 could be involved in mt-membrane potential generation in mtDNA-depleted cells, a feature required to prevent apoptosis and to drive continuous protein import into mt [41]. Besides, in response to cellular stress Clic4 translocates to the nucleus for the control of apoptotic processes [42] making it another pivotal protein of the tianma-activated signalling cascade.
Mki67: The up-regulation of Mki67 (though rather considered as a proliferative marker) has also been observed previously for ginkgo biloba during the stimulation of neurogenesis [43]. The significance of this finding, however, still needs further detailed investigations.
Bax: Bax is a nuclear-encoded protein present in higher eukaryotes that is able to pierce the mt-outer membrane to mediate cell death by apoptosis [44]. However, a recent report demonstrated a non-apoptotic function of Bax in long-term depression of synaptic transmission with caspase-3 activation and Bax modulation as pivotal elements during synaptic plasticity [45]. Thus, fine tuning of bax and caspase-3 may contribute to tianma-mediated synaptic plasticity as part of tianma’s effect on cognitive functions [12].
Decreased levels of GTPases and stress-related proteins in differentiated neuronal N2a cells upon tianma stimulation
Sept2: Septins are an evolutionarily conserved group of GTP-binding and filament-forming proteins that belong to the large superclass of Ploop GTPases. Their expression is tightly regulated to maintain proper filament assembly and normal cellular functions. Septins perform diverse cellular functions according to tissue expression and their interacting partners. Functions identified to date include cell apoptosis, DNA damage response and alterations of these septin scaffolds, by mutation or expression changes, have been associated with a variety of neurological diseases such as AD and Parkinson’s disease (PD) [46,47]. As other Rho GTPases [48,49], Sept2 is crucially involved in modeling neurite outgrowth during neuronal differentiation and a tight regulation of its expression is necessary [50].
Dnm2: Dynamin 2 (Dnm2) is a large GTPase mainly involved in membrane trafficking through its function in the formation and release of nascent vesicles from biological membranes. Additionally, it tightly interacts with and is involved in the regulation of actin and microtubule networks, independent from membrane trafficking processes. Functional data on Dnm2 reveals the possible pathophysiological mechanisms via which Dnm2 mutations can lead to two distinct neuromuscular disorders. Dnm2 mutations cause autosomal dominant centronuclear myopathy, a rare form of congenital myopathy, and intermediate and axonal forms of Charcot-Marie-Tooth disease, a peripheral neuropathy [51,52]. Furthermore, altered expression of Dnm2 has been observed in AD [53].
Wnk1: Wnk1 is a Ser/Thr protein kinase and mutations in the nervous system-specific HSN2 exon of Wnk1 cause hereditary sensory neuropathy type II [54]. Moreover, Wnk1 was identified to interact with Rho-GDI1 to regulate Lingo1-mediated inhibition of neurite extension [55].
Prdx2: Peroxiredoxins are antioxidant enzymes involved in protein and lipid protection against oxidative injury and in cellular signalling pathways regulating apoptosis. In the CNS, Prdx2 has been shown to be expressed in neurons and its de-regulation has been associated with several neurodegenerative diseases such as AD and PD [56-59].
Skp1a: Decreased expressions of the ubiquitin-proteasome/E3 ligase component Skp1a and the chaperone Hsc-70 can lead to a wide impairment in the function of an entire repertoire of proteins in neurons [60] suggesting a new structural role of Skp1a in dopaminergic neuronal functions besides its E3 ligase activity [61]. The close relation between apoptotic and neuronal differentiation pathways raises the question about the significance of tianma-mediated inhibition of Skp1a protein expression in differentiated neuronal N2a cells [62,63].
Hsp90aa1, Hsp90ab1, Hspa4, Hspa5: The heat shock protein (HSP) family has long been associated with a generalized cellular stress response, particularly in terms of recognizing and chaperoning misfolded proteins. HSPs are induced in response to many injuries including stroke, neurodegenerative diseases, epilepsy, and trauma. Hsp70 has a multifaceted role in neurons. It serves a protective role in several different models of nervous system injury. For instance, Hsp70 functions as a chaperone and protects neurons from protein aggregation and toxicity (in PD, AD, polyglutamine diseases, and amyotrophic lateral sclerosis), protects cells from apoptosis (PD), is a stress marker (temporal lobe epilepsy), and also protects cells from cerebral ischemic injury. However, it has also been linked to a deleterious role in some diseases [64,65]. In particular, it has been shown very recently that Hsp70 can suppress AD phenotypes in mice [66]. The main function of Hsp90 complexes is to maintain protein quality control and to assist in protein degradation via proteasomal and autophagic-lysosomal pathways. As such it plays a major role in the pathology of AD where it is crucially involved (with co-chaperones such as the immunophilins FKBP51 and FKBP52) in the control of aberrant phosphorylated tau protein [67]. Thus, alongside Mobkl3 and PP2A, tianma can eventually influence aberrant tau phosphorylation by modulating Hsp90 action [35,36,68].
Canx: Calnexin is an ER-resident molecular chaperone that plays an essential role in the correct folding of membrane proteins and a component of the quality control of the secretory pathway. Canx gene-deficient mice showed that Canx deficiency leads to myelinopathy [69]. In addition, Canx (-/-) cells have an increased constitutively active unfolded protein response (UPR). Importantly, Canx (-/-) cells have significantly increased proteasomal activity, which may play a role in the adaptive mechanisms addressing the acute ER stress observed in the absence of Canx [70]. Besides, caspase-3 or caspase-7 cleaves Canx, whose cleaved product, very interestingly, leads to the attenuation of apoptosis [71].
Trim28: In neurons disruption of Trim28, a key component of transcriptional repressor complexes in the brain, results in increased anxiety-like behavior and sensitivity to stress [72].
Calr: Calreticulin is a soluble calcium-binding chaperone of the ER that is also detected on the cell surface and in the cytosol. The protein is involved in the regulation of intracellular Ca2+ homeostasis and ER Ca2+storage capacity. Calr is also an important molecular chaperone involved in quality control within secretory pathways. As such, it is involved in the folding of newly synthesized proteins and glycoproteins and, together with calnexin (an integral ER membrane chaperone similar to Calr) and Pdia3 (ERp57, an ER protein of 57 kDa; a PDI (protein disulfide-isomerase)-like ER-resident protein), it constitutes the ‘calreticulin/calnexin cycle’ that is responsible for folding and quality control of newly synthesized glycoproteins. In fact, during recent years, Calr has been implicated to play a pivotal role in many biological systems, including functions inside and outside the ER, indicating that the protein is a multi-process molecule [73-75] that might be involved as an ER-resident chaperone in AD and PD [76-78].
Pdia3: Pdia3 is an ER-resident thiol-disulfide oxidoreductase which is modulating Stat3 (signal transducer and activator of transcription) signalling from the lumen of the ER together with Calr [79,80] that might be affected by PD [81].
Gnb2l1: This guanine nucleotide binding protein (G protein), also known as Rack1 (receptor for activated protein kinase C 1), regulates intracellular Ca2+ levels, potentially contributing to processes such as learning, memory and synaptic plasticity by binding specifically to an ionotropic glutamate receptor and thereby dictating neuronal excitation and sensitivity [82].
Atp5a1: Mt-ATP synthase catalyzes ATP synthesis, utilizing an electrochemical gradient of protons across the inner membrane during oxidative phosphorylation. It seems obvious that even intermittent and minor impairment of this highly important enzyme could deprive the brain tissue of energy at crucial times, which may predispose or contribute to neurological diseases [83].
Concluding, our data has shed new insights on the possible involvement of the herb tianma on neuronal functions and its potential effect on signalling molecules critically involved in common neurorestorative processes related to neurodegenerative diseases such as AD, PD or Huntington’s disease (Figure 10). However, further systemic functional in/ex vivo biology studies are required to decipher the functional significance of the individual bioactive components of tianma, by phytochemistry, to unravel their direct effect on neuronal activities related to neuroprotective activities in order to open new potential avenues based on tianma for the possible treatment of neurodegenerative diseases such as AD [4,84,85].
There has been success in our office with PD patients to combine Glutathione or GlutaMax with tianma. Please contact us for more information.
Robin Williams was sober but was struggling with depression, anxiety and the early stages of Parkinson’s disease when he died, his widow said Thursday.
The diagnosis of the progressive illness was “an additional fear and burden in his life,” a person familiar with Williams’ family said on Thursday.
This news hit me particularly hard this week as I grew up on Mork and Mindy and all the amazing movies he stared in since. I have never been so deeply effected by a celebrity’s death like this before. Maybe it’s because I can relate to his challenges with depression as I had a bad case of it several years ago. I can also relate to the chronic illness being a chronic neurological lyme disease survivor. Maybe its also a bit of the fact that I’m invoIved in treating PD in my own practice. I loved his humor and it makes me so sad to think someone that great would do such an extreme thing leaving his kids and wife behind like that. I wonder if I would have been able to reach him in his last hours if things could have been different? Could I have given him some hope?
Anybody who has PD must realize that there is much that can be done most of which is outside the medical care system. The advances in Functional Neurology, Glutathione, and PEMF and just a few. Just take a look at all the video’s on this site and you can see that this disease can be changed for the better.
Parkinson’s disease, depression linked?
Robin Williams’ beloved movie characters
The best Robin Williams tributes
In his own words: Williams on depression
“Since his passing, all of us who loved Robin have found some solace in the tremendous outpouring of affection and admiration for him from the millions of people whose lives he touched,” Schneider said. “His greatest legacy, besides his three children, is the joy and happiness he offered to others, particularly to those fighting personal battles.
Comedic actor Robin Williams dies
“Robin’s sobriety was intact and he was brave as he struggled with his own battles of depression, anxiety as well as early stages of Parkinson’s disease, which he was not yet ready to share publicly.”
“It is our hope in the wake of Robin’s tragic passing, that others will find the strength to seek the care and support they need to treat whatever battles they are facing so they may feel less afraid.”
Williams had been active as an actor in the last year of his life, performing in a CBS sitcom that was canceled this year and acting in four films that have yet to hit theaters.
It is not clear whether the early-stage Parkinson’s disease affected his ability to work.
“Friends and family can usually detect changes in the Parkinson’s patient including poor posture, loss of balance, and abnormal facial expressions,” according to the National Parkinson Foundation. “During this initial phase of the disease, a patient usually experiences mild symptoms. These symptoms may inconvenience the day-to-day tasks the patient would otherwise complete with ease. Typically these symptoms will include the presence of tremors or experiencing shaking in one of the limbs.”
Parkinson’s disease “causes certain brain cells to die,” according to the website of the National Institutes of Health. It is more likely to affect men than women and most often develops after age 50.
Williams used exercise and cycling to manage his stress and depression, and the prospect that the illness would prevent him from doing that was extremely upsetting, adding to the depression, the person familiar with his family said.
What is Parkinson’s disease?
Fellow actor Michael J. Fox, who has Parkinson’s and established the Michael J. Fox Foundation, said Thursday that he was unaware of his friend’s condition.
“Stunned to learn Robin had PD. Pretty sure his support for our Fdn predated his diagnosis. A true friend; I wish him peace,” Fox tweeted.
Investigators believe Williams used a belt to hang himself from a bedroom door sometime between late Sunday and when his personal assistant found him just before noon Monday, according to Marin County Assistant Deputy Chief Coroner Lt. Keith Boyd.
Boyd would not confirm or deny whether Williams left behind a letter, saying that investigators would discuss “the note or a note” later.
The coroner’s investigation “revealed he had been seeking treatment for depression,” Boyd said.
He spent time in a treatment facility in July, a time when his wife and representative have said he was battling depression.
Media reports at the time speculated that Williams had resumed drinking alcohol, but the statement from his wife appears to dispute those reports.
Williams entered rehab because of drug and alcohol addiction at least twice previously.
“Robin spent so much of his life helping others,” his wife said. Whether he was entertaining millions on stage, film or television, our troops on the front lines, or comforting a sick child — Robin wanted us to laugh and to feel less afraid.”
Dr. John, I am sitting in my home in Texas considering the events of this past week. As I become more and more aware of how much better I feel physically and mentally, I am overwhelmed with emotion! Thank you from the bottom of my heart for what you do! I have so much hope for the future! Praise God, that you are using your gift He has bestowed upon you! You are doing a monumental work! Your friend, CG- Texas
Functional Cranial-Release is the art and science of restoring normal brain and nervous system function by using Functional Neurology along with Specific Endo-nasal balloon manipulation to do the following:
1) Restore the brains ability to oxygenate itself through both improving air flow into higher area’s through the nasal passage and also improve the normal pumping action inherent in all of use (cranial rhythm) that moves nutrients such as oxygen and neurotransmitters that bath the central nervous system keeping it healthy.
2) Utilize neurologic testing to determine the pathways and brain centers that are either firing to much or firing too little using the following; Use of theC.A.P.S. Balance Plate for brain function, Saccadometerwhich uses a laser to test eye motion which, can be important to make discovery as to the exact location and sidedness of the brain problem. Examination of your eye’s movements and reflex’s, your muscles or motor system, the autonomic nervous system, your circulation, your sensory system, the vestibular system (or) your ability to balance [many times using a computerized balance platform]. Through the specific use of various modalities such as one or more of the following; Very Specific Chiropractic Adjustments of the spine, extremities, and cranium, Soft Tissue or Massage, Eye Pattern & Eye Exercise’s, Canalith Repositioning (or) Eply’s, Vestibular Rehabilitative Modalities or VRT, and many others too numerous to list. The modalities used depend on the specific needs of the patient.
3) A series Cranial Release’s are performed where the connective tissues that surround your brain and spinal cord called the Dura Mater are specifically released using endonasal balloon inflations. This is done in combination with the above mentioned functional neurologic modalities to provide the therapeutic effect to balance and normalize brain function. This normalization results in healing.
Recent studies in the Parkinson’s disease literature have cited a tuberculosis-like germ called nocardia as being responsible for Parkinson’s of unknown cause (Kohbata and Shimokawa, 1993) (Beaman, Beaman and Kjelstrom, 1994) (Kohbata and Beaman, 1991). Kohbata seemingly cemented a relationship between nocardia and Parkinson’s by finding serologic evidence in 20 of 20 Parkinson’s patients. With this finding, Kohbata acknowledged that blood tests for nocardia and the mycobacteria such as tuberculosis often cross-react, as they belong to the same order of bacteria, the Actinomycetales. Besides this difficulty in differentiation, a well used medical school textbook of microbiology points out that even among experts, different observers may classify the same strain of bacteria as nocardia or Mycobacterium tuberculosis (Atlas, 1988). To add to existing difficulties, both microorganisms can be “acid-fast,” retaining a characteristic reddish color after being washed with acid alcohol, a common laboratory reagent. Such a staining characteristic has long been used to identify Mycobacterium tuberculosis.
NEW ORLEANS, LA – May 22, 2011 — The stomach bacteria responsible for ulcers could also play a role in the development of Parkinson’s disease according to research presented today at the 111th General Meeting of the American Society for Microbiology.
“Infection of late middle-aged mice with a particular strain of the bacteria Helicobacter pylori results in development of Parkinson’s disease symptoms after 3-5 months,” says Traci Testerman of Louisiana State University Health Sciences Center, Shreveport, who presented the research. “Our findings suggest that H. pylori infection could play a signficant role in the development of Parkinson’s disease in humans.”
Physicians have noted a correlation between stomach ulcers and Parkinson’s disease as far back as the 1960s, before it was even known that H. pylori was the cause of ulcers. More recently, a number of studies found that people with Parkinson’s disease were more likely to be infected with the bacterium, and that Parkinson’s patients who were treated and cured of infection showed slight improvement compared to controls that continued to deteriorate.
In Guam, a study of why some populations had a high risk of developing a Parkinson’s-like disease discovered that a specific compound in cycad seeds eaten by these populations was neurotoxic. The compound, which resembles a cholesterol with an attached sugar group, is almost identical to a compound produced by H. pylori.
Testerman and her colleagues developed an animal model to more effectively understand the role of H. pylori and its modified cholesterol in Parkinson’s disease. They infected young and aged mice with three different strains of the bacteria and monitored their locomotor activity and dopamine levels in the brain. Mice infected with one of the strains showed significant reductions in both.
“The results were far more dramatic in aged mice than in young mice, demonstrating that normal aging increases susceptibility to Parkinsonian changes in mice, as is seen in humans,” says Testerman.
In order to determine whether the modified cholesterol or other substances could be responsible for Parkinson’s disease development, they fed aged mice with H. pylori extracts. The mice did not become infected but developed the same symptoms as those infected with the bacteria, suggesting that the modified cholesterol or some other product contained within the bacteria contribute to disease development.
“Our mouse model demonstrates a direct effect of H. pylori infection on the development of Parkinson’s disease. The observation that not all H. pylori strains are equally able to cause symptoms will allow us to investigate bacterial factors and/or immune response to H. pylori infection that increase the risk for Parkinson’s disease,” says Testerman.
The below video was made by a college of mine. He is a fellow Functional Neurologist and did such a good job at explaining how Dopamine when not properly metabolized can become a source of the problem. What happens is the Dopamine when oxidized or acted on by chemicals and toxins in your brain can become dopamine quinones which damage brain cells. This is why L-dopa can increase the rate of death of the very nerves we are trying to save. So in order to stop shaking we cause our disease to progress more rapidly. Both Methylation and too much MOA action can be the issue the has caused the brain disorder to begin with and these can be treated with natural nutrients and dietary changes along with Glutathione suppositories. Glutathione it the brains master anti oxidant and will protect your brain from this cascade. Take a look at GlutaGenic.com for product information.
