From stomach to the brain: The evolution of Parkinson’s disease!

Dedicated to Dr. Peter Moran, a close friend of mine who’s has just been diagnosed with Parkinson’s disease, but he will fight it.


Parkinson’s disease that has affected celebrities such as Muhammad Ali and Michael J Fox even at an early age than usual, was first described in 1817 by the English physician, James Parkinson, who initially called it paralysis agitans. (1) Parkinson described six cases with the disease, having classic symptoms of resting pill rolling tremor, abnormal posture and gait, paralysis and diminished muscle strength, with progression of the disease over time. (2) Later on, other neurologists, most notably Jean-Martin Charcot, the father of modern neurology, in his studies between 1868 and 1881 elaborated further on the understanding of the disease, and made the distinction between rigidity, weakness and bradykinesia, and renamed the disease in the honor of James Parkinson to “Parkinson’s disease” (1) In 1912 Frederic Lewy discovered the “Lewy bodies”, microscopic particles in the brains of these patients and in 1919, Konstantin Tretiakoff, reported that the substantia nigra was the main cerebral structure affected. (1) Levodopa, the main medication treatment for Parkinson’s, that increases the level of dopamine, deficient in the brain of subjects was actually first synthesized in 1911, but was not used in the treatment until 1967.(3)

Over time it was established that Parkinson’s disease is not only a movement disorder, presenting with hand tremors and bradykinesia or slow movement, and rigidity, but it is a progressive brain degenerating disease that ends in the dysfunction of higher cortical functions, leading to depression and dementia as well. This disease is the result of loss of dopamine-generating cells in substantia nigra of midbrain, caused by the accumulation of some proteins called Lewy bodies inside the neurons. (4) But there are many conditions looking like Parkinson’s disease, specially in regard with its movement disorder, that are collectively called “Parkinsonism”. This could be caused by a variety of known and unknown causes, e.g. infections such as AIDS and different encephalitis; toxins e.g. carbon monoxide, carbon disulfide, manganese and mercury; Paraneoplastic syndrome caused by antibodies associated with cancers; drug-induced e.g. antipsychotics and anti-emetics such as metoclopramide; vascular Parkinsonism associated with cardiovascular diseases; and punch drunk syndrome or Boxing Parkinsonism, etc. (5-6)    

 Parkinson’s disease is considered to be “idiopathic” in contrast with the secondary parkinsonisms that have known causes, which in fact “idiopathic” due to our lack of knowledge about its real etiology. Genetics has a very minute role in Parkinson’s disease, i.e. 5-10%, surprisingly in contrast with other neurological or psychiatric disorders that may carry multi-genetic or epigenetic mode of inheritance, exhibiting a classical Mendelian type of inheritance. Nowadays, six genes, alpha synuclein, LRRK2, VPS35,Parkin, PINK1 and DJ-1, have definitely been associated with an autosomal dominant or recessive mode of inheritance in familial parkinson’s. (7) Lewy bodies the cardinal patho-histological feature of Parkinson’s disease is in fact an eosinophilic cytoplasmic inclusion aggregation of proteins (primarily alpha-synuclein) that in a highly regulated process, displace the dopamine containing neurons. The mere fact of such regulated killing machinery of the neurons of substantia nigra and other regions of the brain could be common sensibly discerned to have been done by actively programmed invasions of sophisticated organisms, that I will detail in the following.  

 In the search of a viral cause:

Parkinson’s disease like many other neurological or psychiatric disorders, such as Alzheimer’s disease, Multiple sclerosis, Autistic spectrum disorders, schizophrenia and bipolar disorder that I have detailed elsewhere (8-12), have no immediate or acute cause to be discovered easily. In other words, the causes of all such disorders need to be probed in the past, decades or generations ago. Parkinson’s disease like these disorders share an inflammation/infection causation long before the production of the disease process or clinical manifestations. In fact Parkinson’s disease is one of the few of such disorders with strong consensus on such etiology that I will attempt to detail here. As early as 1963, Parkinson’s disease has been linked to infections, specially the influenza epidemic of 1918-1921. (13) The frontier study by Poskanzer and Schwab in 1963 reported that about 40 years after the epidemic, the clinical signs and symptoms of Parkinson’s emerged in their study cohort, with only 11.2 % of the subjects gave a history of encephalitis at the time of initial epidemic infection. But the authors prematurely thought of the influenza epidemic as the sole cause of Parkinson’s, so they predicted that by 1980’s the prevalence of the disease with drop, but such did not befall!        

Further search for the etiology of Parkinson’s disease, continued in the viral domain due to the neurotropic virulence of different viruses, causing encephalitis and consequentially neurological disorders such as Parkinson’s disease. (14) Among these neurotropic viruses, herpes simplex virus (15-17); Epstein-Barr virus (18-19); Cytomegalovirus (20); Varicella zoster virus (21); Borna virus (22); Measles (23); Coxsackie virus (24-6); Echo virus (27); Polio virus (28); Human Immunodeficiency Virus (HIV) (29-32); West Nile virus (33); Japanese encephalitis B virus (34-5); St. Louis virus (36-7); Hepatitis B & C viruses (38); paratubercluosis virus (39); and of course more search for the influenza viruses, even in the mild and seasonal flu forms have been suspected, studied and reported. (40-7) But many of these viral insults appear to have caused parkinsonism or secondary Parkinson’s diseases or Parkinson’s symptoms than the so called idiopathic Parkinson’s disease with its characteristic Lewy bodies histopathology.    

Therefore the research on proving a viral etiology of Parkinson’s disease have not been as conclusive as it has been in the case of other disorders of the brain either neurological or psychiatric! In fact some studies to the surprise have found a reduction of the risk of Parkinson’s disease associated with most childhood viral infection, particularly measles. (23) Some of these viral researches have made the distinction between the different varieties of encephalitis well known caused by different viruses, such as encephalitis lethargica, or Von economo’s from Parkinson’s disease. (26) Many of these viral encephalitis seem to have different clinical presentations, course and progression of the illness, pathophysiology and histopathology, though share some common features with Parkinson’s disease.        

Among all the viral studies causation link with Parkinson’s disease still stands the original suspicion of the influenza virus, dating back to the epidemic of 1918-20, basically for aging and progression of the disease matching 40 years after in the off springs of the infected mothers. (48) But the un-answered big questions have been first the failure to detect virus particles in the brains, or antibodies in the serum or cerebrospinal fluid of patients with Parkinson’s disease. (46) Also the overlapping of such gestational influenza infection with other neurodevelopmental disorders such as schizophrenia. In a better word, what has or have been the determining or precipitating factor(s) to cause one or not the other! (10-11)

 Yamada early on in 1996 in answering the above dilemma after an immunohistochemical work on animal model of Parkinson’s disease, injecting influenza virus to rats, proposed that an immunological hypothesis through induction of interferon by the virus causing Lewy bodies and hence later death of substantia nigral neurons and the evolution of Parkinson’s disease! (49) Along this line of thinking and search for a viral etiology, recently Bobyn and colleagues (50) in their animal model of producing Parkinson’s injected to the mice’s supra-nigral brain region, a double-stranded RNA viral analog, followed 2, 7 or 14 days later by administration of the pesticide, paraquat, to prove an interaction between the viral particles and environmental toxins such as pesticides to the cause of Parkinson’s disease. Although this viral-toxin combination, augmented neuronal loss and microglial activation, but failed to affect home-cage activity, striatal dopamine terminals, or subventricular neurogenesis, to prove the concept.

 Inflammatory and immunologic evidences:

Although viral invasions as etiology to the evolution of Parkinson’s disease have been for more than half a century inconclusive, but the evidence to the neuronal, even systemic inflammation and the immunologic impact in the subjects with the disease have been undeniable. Hoffman and colleagues as early as 1981 have reported that serum IgA being higher and IgM lower than normal, with IgM decreasing with age in parkinsonism-dementia. (51) Serum immunoglobulin (Ig) levels did not correlate with the duration of the disease and the differences in viral antibody titers nor the presence of autoantibodies or circulating immune complexes could account for the variations in serum Ig levels between patients and controls. Thus these researchers conclude that differences in serum Ig levels in the patients were probably due to repeated infections and abnormal immunoregulation accompanying immunodeficiency during the course of the disease rather than to a specific antiviral or autoimmune response.

 Fiszer and colleagues (52) among others have reported immune abnormalities, including the occurrence of autoantibodies against neuronal structures and abnormal T cell functions in Parkinson’s disease. Gamma delta+ T cells which is considered to play important role in immune responses in infections and autoimmunity, were reported by these researchers to be increased in the blood and cerebrospinal fluid (CSF) from patients with Parkinson’s disease. Yamada and colleagues (53) have reported Lewy bodies in the substantia nigra of Parkinson’s disease subjects to be positive for MxA, that is the induced protein of alpha-interferon that is a protein secreted by the immune system against infections. Wilfried and colleagues (54) have also reported that Selegiline, a monoamine oxidase-B inhibitor stimulates biosynthesis of cytokines interleukin-1 beta and interleukin-6, both essentials in the body’s autoimmune and anti-inflammatory responses to bacterial or viral infections. A report also by Hisanaga and colleagues (55) show increase in activities of a group of T-cells as part of post-infectious immune response in Parkinson’s disease. Członkowska and colleagues (56) hypothesize that mitochondrial mutations, oxidative stress, microglial reactions and apoptosis in the region of substantia nigra of Parkinson’s disease are all caused by inflammatory reactions of immunoglobulin synthesis, cytokines, T-cell activations and production of interferons, and suggest treatment with anti-inflammatory drugs to slow progression of the disease.

Chi and colleagues (57) have also hypothesized that Aquaporin-4 (AQP4), a protein highly expressed in mammalian brains and involved in the pathophysiology of several brain disorders, its deficiency in mouse models of Parkinson’s disease, is associated with microglial inflammatory responses and severe loss of dopaminergic neurons. Recently Ferrari & Tarelli (58) have shown that systemic or peripheral inflammations could trigger exacerbation or transformation of a “primed” microglia into an “active” state, through induction of the synthesis of cytokines in the brain, that explains the progressive nature of neurodegenerative disorders such as Parkinson’s disease by the way of neurodegeneration of neurons in the substantial nigra. These researchers once again suggest the anti-inflammatory treatment in Parkinson’s disease may exert a neuroprotective effect. Along this line, Umemura and colleagues (59) have reported that C-reactive protein (CRP), a serum inflammatory biomarker, is not only associated with Parkinson disease, but increases with the progression and worsening of the disease in real patients, so a simple biomarker of neuroinflammation and acceleration of dopaminergic neurodegeneration. Although lowering the systemic or peripheral anti-inflammatory treatment in Parkinson disease may slow the progress of the disease to certain degree, it would not probably stop or reverse a pathological process that has been prompted long time ago before the onset of the illness. Therefore some researchers have suggested initiation of immunotherapy in Parkinson’s disease similar to that already existed in the treatment of other autoimmune disorders such as Multiple Sclerosis (60). Hutter-Saunders and colleagues (61) in their laboratories have sought to transform autoreactive adaptive immune responses into regulatory neuroprotective cells in Parkinson’s disease. In this context, these researchers hope by induction of immune responses against modified or misfolded brain proteins such as alpha-synculein serves to break the immunological tolerance, while eliciting adaptive immunity to facilitate neuronal repair.

 In summary so far, we are well aware of the histopathology of Parkinson’s disease by the evidence of misfolded or mutated alpha-synculein proteins that are observed inside the Lewy bodies, pathognomonic of the disease. We have also inevitable evidence of neuro-inflammation and auto-immune response to latent infections of the brain that intermittently and repeatedly damage the protective proteins of the neurons subclinically over a long life span, hence damage the brain cells of substantia nigra as example and cause the Parkinson’s disease. (61) This fact has been shown through animal models of Parkinson’s disease by induction of the disease pathology (mutation of alpha-synculein proteins) by lentivruses with their characteristic long incubation periods. (62) These animal studies have shown overexpression of alpha-synuclein inducing a time-dependent neuropathological changes reminiscent of Lewy pathology: abnormal accumulation of alpha-synuclein in cell bodies and neurites, alpha-synuclein-positive neuritic varicosities and cytoplasmic inclusions that stained with ubiquitin antibodies and became larger and more frequent with time. Most recently in December 2015, Beatman and colleagues (63) have reported that neuroinvasive viruses, while capable to infect neurons and cause severe diseases such as encephalitis, only select and not all neurons are infected, implying that neurons exhibit innate resistance to viral infections. These researchers have discovered that native neuronal expression of alpha-synuclein protein involved in the pathogenesis of Parkinson’s disease inhibit viral infection in the central nervous system, but in the absence of alpha-synuclein protein, mice exhibited significantly decreased survival, markedly increased viral growth in the brain, and evidence of increased neuronal injury. So in a better word, this means that the damaged alpha-synculein inside the Lewy bodies in Parkinson’s disease, is a solid manifestation of the injury of a protector of the brain, in the war against microbial invasions.  

In the following in the search for the exact offensive agent to the substantia nigra of the brain to cause Parkinson’s disease, I will review the literature on the bacterial world with the hope to find this enemy.

 The enemy from within:

While viral studies failed to find any causation link between viral insults and formation of Lewy bodies so to prove a viral connection in Parkinson’s disease, bacterial studies were able to do so somewhat as early as 1993. Kohbata & Shimokawa from Japan in 1993 (64) reported that Nocardia, a genus of aerobic Gram-positive bacteria, which were known earlier causing encephalitis with parkinsonian features, could in sublethal doses cause an L-DOPA-responsive movement disorder with Lewy-like bodies in mice. In their study these researchers detected antibodies to nocardia in the serum of all 20 patients with Parkinson’s disease as well. Two years later, Hubble and colleagues in US in an attempt to reexamine such causation link with Nocardia, failed to find so in comparison with normal controls. These researchers found a high exposure rate of humans to nocardial antigens, especially among men and older individuals, though they admitted that their serological testing may not have been optimal for detection of nocardial central nervous system infection.

 A year later in 1996, de Pedro-Cuesta and colleagues (66), reported of another aerobic bacteria, but gram negative, the common Bordotella Pertusis, causing whooping cough in the young children all over the world could be causally linked to Parkinson’s disease. These researchers in an Islandic cohort born between 1869-1927 found an increase of the risk of Parkinson’s disease years after during the period of 1954-1963. But late on Fiszer and colleagues (67) from Poland, found no such a link or significant difference between the Parkinson’s patients and controls in regard with serum antibodies to whooping cough. Carvey and colleagues (68) have proposed the common complication of pregnancy with bacterial vaginosis which is known to produce increased levels of , lipopolysaccharide (LPS) and pro-inflammatory cytokines in the chorioamniotic environment of the fetus, could be a risk factor for Parkinson’s disease later on in life.

 In recent years, there have been a few reports of causal link between Parkinson’s disease and Toxoplasma gondii that is a relatively common parasitic invading agent to the brain. Miman and collegues (69) from Turkey in 2010 claimed such causation by finding anti-T. gondii IgG antibodies in Parkinson’s patients, but in the same year, Celik and colleagues (70) from Turkey as well in a different laboratory refuted such claim and found no statistically significant association between T. gondii and idiopathic Parkinson’s disease. More recently Harris and colleagues (71) from Canada, while confirmed a correlation between severe influenza and Parkinson’s disease, they proposed that additional exposure to other environmental toxins, such as animals’ exposure through bacterial endotoxin, could complete the puzzle. Fungal infections of the brain and even scrub typhus in case reports have also been reported to cause, if not Parkinson’s disease, but parkinsonism or parkinsonian symptoms. (72-4)

 Despite lacking any robust evidence of the link between Mycobacterium tuberculosis infection and Parkinson’s disease, common antibiotics such as Isoniazid and Rifampicin, used extensively in the treatment of such infection, have been shown to exhibit neuroprotective effects in Parkinson’s disease as early as 1988. Gershanik and colleagues in 1988 (75) reported improvement with Isoniazid in the levodopa-induced dyskinesias in 20 patients with Parkinson’s disease, but the benefits were markedly reduced in 18 patients within the first few weeks of treatment. This effect was accompanied by an intolerable worsening of parkinsonian signs. Recently Bi and colleagues (76) have reported that Rifampicin protects the neurons against apoptosis or brain cells death and inhibit the expression of α-synuclein multimers. These researchers also report that Rifampicin is capable of reducing microglial inflammation and improving neuronal survival shown in their laboratories under a variety of experimental conditions, and suggest that it may be useful in Parkinson’s therapeutics.

Epidemiologic studies of Parkinson’s disease globally have helped to narrow down the search for the cause of this disease. The prevalence of Parkinson’s unlike other neurological or psychiatric disorders such as Schizophrenia or Alzheimer’s seems to not be equally distributed world-wide. The prevalence of Parkinson’s disease has been reported to range from 15 (per 100,000 population) in China to 657 in Argentina in door-to-door surveys and to vary from 100 to 250 in North America and Europe. (77-8) An early study in 1996 by Altschuler (79) reported a higher prevalence of gastrointestinal ulcers, caused by Helicobacter pylori infection, than in age- and sex-matched controls in Parkinson’s disease patients. Helicobater Pylori, a gram negative microaerophilic bacteria, had just been discovered a decade earlier, in 1982 by the Australian scientists Barry Marshal and Robin Warren to cause chronic gastritis and gastric or peptic ulcer. (80) This bacteria that believed to belong to the group of Campylobacter and was called C.Pylori, was identified by Goodwin and colleagues in 1989, to be different, so was classified under Helicobacter pylori. (81) This shook the medical world and the treatment of gastric and duodenal ulcers that had been for years by antacids and gastro-intestinal pump blockers, switched to antibiotics with great success. More than 50% of the world’s population harbor H. pylori in their upper gastrointenstinal (GI) tract, more prevalent in the developing countries, with up to 85% of infected people lacking any symptoms. (80, 82) The prevalence dispersion of this bacteria globally in its human host, has resulted in a distinct phylogeographic pattern that can be used to reconstruct both recent and ancient human migrations, as it has been reported in the journal of Science this January 2016 on a 5300-year-old H. pylori genome from a European Copper Age glacier iceman mummy. (83)  

 Soon not H.Pylori was repeatedly reported more frequent in Parkinson’s patients, but even in their siblings who shared some parkinsonian features as well. (84) H.Pylori in Parkinson’s was not just present, but increasing with age, through antibody titers rising from 30 to 90 years. (85) This followed by the studies showing the improvement in Parkinson’s symptoms severity by eradication of H.Pylori and also better and prolonged response to L-dopa. (86-9) In contrast the presence of untreated H.Pylori caused reduction of levodopa absorption in Parkinson’s disease patients and hindering their improvement. (90) Since H.Pylori, as the most common pathogen in humans does not lead to the evolution of Parkinson’s disease in everyone, common immunological and inflammatory predisposing factors and environmental toxins such as cycads have been attempted to explain the missing causal link between parkinsonism and H.pylori infection. Cycads are seed plants, looking like ferns and palms, but totally different with a long fossil history, formerly more abundant and more diverse than they are today, with little changes since the Jurassic time. Cycads grow very slowly and live very long, with some up to 1,000 years, in different conditions, even on rocks and in sands and poor oxygen situations. Cycad seeds produce a neurotoxin, called BMAA that if eaten by humans can cause neurological diseases. Moreover cyanobacteria similar to H.Pylori, are also living in the roots of cycads. (91) Schulz and colleagues (92) have proposed a “cycad theory” through their recent experiments on mice fed cycad displaying behavioural symptoms of parkinsonism such as reduced gait length, as well as neuropathological signs such as a loss of striatal dopaminergic terminals and an upregulation of the dopamine D2 receptor. These effects causes by cycad-derived sterol glucosides are structurally similar to cholesterol glucosides that account for a significant part of the lipid profile of H. pylori.

 Dobbs and colleagues (93) from the Clinical Neuropharmacology section at the King’s College in London, after years of working on linking H.Pylori with Parkinson’s disease have recently proposed an explanation of the disease causation that happens only in a minority of infected hosts. These researchers challenging the concept of idiopathic parkinsonism as inevitably a progressive neurodegenerative disease, have proposed a natural history of sequential microbial insults with predisposing host response. The conversion of “malignant” to the “benign” form of the disease, improvement in brady/hypokinesia after eradicating “low-density” H.Pylori infection, the probability of having the Parkinson’s correlating to the serum level of H. pylori antibody profile, and clinically relevant gradients between this “discriminant index” and disease burden and progression, all point to an autoimmune susceptibility in certain individuals. More specifically Parkinson’s subject have prodromally sings and symptoms of persistently abnormal bowel functions, specific abnormal duodenal enterocyte mitochondrial morphology, and high H. pylori antibodies’ titers. The progression of H.Pylori’s infection is also observed clinically and prodromally from an initial slow intestinal transit manifestation as “constipation” to “diarrhea” indicating the involvement of the secondary small-intestinal bacterial overgrowth. (93) The same research team have more recently (94) shown the efficacy of eradication of H.Pylori in symptoms improvement in Parkinson’s without the use of conventional anti-parkinsonian medications with the persistence of the clinical response even more than three years after the eradication.

 Dobbs and colleagues have also argued against the progression of Parkinson’s from brady/hypokinesia to rigidity, as antibiotic treatment of H. Pylori eradicates the bacteria in the stomach and improves brady/hypokinesia but causes its overgrowth in small intestine and worsens the rigidity. (93) More recently this research group have attempted to explain this differential phenomenon in connection between H.Pylori and Parkinson’s disease brady/hypokinesia and rigidity symptomatology. This differential effect of Helicobacter pylori eradication on parkinsonian symptoms has been in part explained by serum vitamin B(12) that is utilized more by the overgrowth of the bacteria in small intestine that provides a source of inflammation to drive homocysteine production and hyperhomocysteinaemia that is common phenomenon in Parkinson’s disease. Moreover the intestinal bacaterial overgrowth and rigidity symptoms are histologically associated with clouds of lysosomes seen in duodenal enterocytes, increase in natural killer and T-helper blood counts, and hydrogen breath test positivity for overgrowth of H.Pylori. (95)

Although as it has been suggested, H.pylori infection could be a secondary condition in Parkinson’s disease due to gastrointestinal motility abnormalities existing in this disorder, favoring the occurrence of local infections. (96) But there are a few distinct differences between general subjects with pylori infections than Parkinson’s, e.g. higher prevalence of small intestinal bacterial overgrowth, and the eradication of small intestinal bacterial overgrowth leading to improvement in motor fluctuations of Parkinson’s without affecting the pharmacokinetics of levodopa. Moreover infection with H. pylori persists throughout life, resulting in a common chronic inflammatory response with local secretion of numerous inflammatory mediators including chemokines [interleukin (IL)-8, macrophage chemotactic protein (MCP)-1, growth-regulated oncogene (GRO)-α] and cytokines [IL-1β, tumor necrosis factor (TNF)-α, IL-6, IL-12, interferon (IFN)-γ], which all could be a common denominator for precipitation of many disorders including neurological not limited to Parkinson’s disease. (97) A recent large Danish study, comprised of 4484 Parkinson’s patients and 22, 416 population controls between 2008-11, revealed that prescriptions for HP-eradication drugs and proton pump inhibitors, 5 or more years prior to the diagnosis of Parkinson’s were associated with a 45% and 23% increase in the disease risk respectively. (98) Furthermore Parkinson’s patients with H.Pylori have more severe symptoms than non-infected ones. (99) Also the presence of pervasive α-synuclein deposition in the gastrointestinal tract strongly implicates the GI system in the pathogenesis of Parkinson’s disease. (100) Finally in regard with H.Pylori, Dobbs and colleagues (101) in this month of February 2106, have raised a gaserointestinal microbiome as the aetiopathogenic model for the spectrum of Parkinson’s disease.

These researcher propose the concept that systemic immuno-inflammatory processes including the ones in GI system mediate neuro-inflammation including the one in Parkinson’s disease. (102) This model is based on an interaction between GI infection/inflammation, systemic immuno-inflammatory response or autoimmune, and human genetics. This theoretical model has been rooted in the evidence that peptic ulceration is prodromal to PD, hypokinesia improves with the biopsy-proven Helicobacter pylori eradication, but worsening of rigidity symptoms, independent of any antiparkinsonian medications.

 To better understand the pathophysiology of Parkinson’s disease, the research have recently centered more on the role of Prions in the causative process of the disease. Neurodegenerative diseases such as Parkinson’s are caused by proteinaceous aggregates, and in case of Parkinson’s disease, the misfolded of alpha-synculein protein and formation of Lewy bodies. As the prevalence of hereditary or familial Parkinson’s is in minority, the horizontal transmissibility of this disease is very probable. This transmissibility has been evidenced through “Prions”, which are infections protein (a combination of word protein and infection). Prions that were initially discovered in bovine spongiform encephalopathy or “mad cow disease” and later on in a human encephalopathy, Creutzfeldt-Jacob disease, have also been proposed in the pathophysiology or Parkinson’s disease. (102) Recently it has been suggested that such infective prions from the environment, e.g. of animals could be transmitted into humans through our GI system. (103) This is in line with the evidence in the autopsies of Parkinson disease patients that Lewy bodies had formed on healthy embryonic neurons which had been grafted onto the brain tissue of the patients several years prior to the said examination. (104-5) hereby it may be also possible that α-synuclein transmitted from diseased to healthy neurons, suggesting that Parkinson disease may be transmissible from a Parkinson disease patient to a healthy individual. (106)

 The prion proteins through ferritin, a protein available in foods and resistant to digestive enzyme hydrolysis, and homologous across many species and acts as a co-transporter and facilitator of enterocyte internalization of the infectious prion, are transmitted to susceptible hosts. (107-8) Due to the commonality of H.Pylori, prion proteins and their feasible transportation through common ferritin in foods across species, one may suspect that there must be some protective factors to prevent many from having prion or neurodegenerative diseases such as Parkinson’s. One such important group factors are the individual susceptibilities, specially at the GI, neuronal, and immune levels. The other one is “autophagy”, that has been observed neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s diseases as well as prion diseases. Autophagy is a highly conserved homeostatic process by which several cytoplasmic components (proteins or organelles) are sequestered in a double-membrane-bound vesicle termed ‘autophagosome’ and degraded upon their fusion with lysosome. The pathway of intercellular self-digestion at basal physiological levels is indispensable for maintaining the healthy status of tissues and organs. In case of prion infection, increasing evidence indicates that autophagy has a crucial ability of eliminating pathological prion proteins accumulated within neurons. In contrast, autophagy dysfunction in affected neurons may contribute to the formation of spongiform changes. (109)

 Lastly to weave the H.Pylori infection in the gastrointestinal (GI) system with the infective prion proteins that are transmitted to the susceptible hosts, there is evidence of the existence of Lewy bodies which is contained alpha-synuclein protein, the pathological hallmark of Parkinson’s in the intestinal enteric nerves of such patients. Therefore there is strong evidence that GI tract might be an early site of Parkinson’s seeding in response to an environmental toxin or pathogen. There is also strong evidence that in Parkinson’s there is an increased intestinal permeability (gut leakiness) to proinflammatory bacterial products, prions and toxins that make the pathway from the stomach to the brain easier for microbial invasion. In addition, this intestinal hyperpermeability significantly correlated with increased intestinal mucosa staining for gram negative bacteria and tissue oxidative stress, in Parkinson’s subjects. (110)

 From stomach to the brain: The evolution of Parkinson’s disease

In conclusion, the vast literature on Parkinson’s disease, with a very high consensus, suspect this common neurodegenerative disease, have been caused by some environmental invasions. These invasions, no matter the nature of the microbial agent(s), lively or prion-like seem to pass on to the substantia nigra neurons through our stomach and intestine. This could have been done directly by infecting agents such as H.Pylori that is very common in humans, but causing the disease only in susceptible individuals. Another possibility is the transportation of infecting agents such as prion proteins through foods to the GI system and from there to the brain again in susceptible subjects. Either ways, the research summarized somewhat here, refute that Parkinson’s disease is idiopathic or in majority genetic, hence untreatable or unpreventable. In either ways, Parkinson’s disease is not only treatable, as many studies reported here have shown, by antibiotics or anti-inflammatory agents, but preventable by preventing the GI infections. What we know for certain is that H.Pylori needs to be seriously treated and prevented. We also need to break the transmission of the infecting agents’ cycle to susceptible hosts, by identifying the infecting prion proteins in foods, animals or other environmental sources. Finally we need to screen susceptible individuals and promote their immunity, by vaccinations, immunotherapy or else!   

Dr.Mostafa Showraki, MD, FRCPC                                                               Lecturer, School of Medicine, University of Toronto,Author: “ADHD:Revisited” Book/ “”/””


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