Parkinson's Disease, cause in the brain or gut?

"All diseases start in the gut" - Hippocrates 

The microbiota and microbiome has been a really hot research topic the last decade. Recent research shows that gut-brain interactions might be influenced by someone's microbiota conditions. Besides, recent studies show that the gut-brain axis, including the autonomic and enteric nervous system, and the microbiota might be affected in Parkinson's disease (PD) [1].

Parkinson's disease is the second most common age-related neurodegenerative disorder after Alzheimer's Disease. It is estimated that seven to ten million people worldwide have Parkinson's Disease [2]. PD is characterised by classical motor symptoms like bradykinesia, tremor, rigidity and postural instability. In addition, patients have non-motor symptoms that involve the gastrointestinal tract, urogenital and cardiovascular system [1].

Gastrointestinal (GI) complaints are a well-known problem in PD, 80% of all PD patients show symptoms in the GI tract [3]. The study of Edwards et al. shows that symptoms like abnormal salivation, dysphagia, nausea, constipation and defecatory dysfunction were present in respectively 70, 52, 24, 29 and 66 percent. These symptoms were only caused by PD itself and no correlation was found with the participants' age or other possible confounding factors [4].

The exact cause of PD is unknown although possible risk factors and pathophysiological features have been discovered. An important pathological feature is a reduced amount of dopaminergic neurons in the substantia nigra, which leads to disorganisation in the basal ganglia (BG) circuits. The substantia nigra is part of the basal ganglia which are responsible for i.e. the motor control, emotional and cognitive functions. Disorganisation in the BG leads to disturbed subcortico-cortical interactions. This leads to the classical motor symptoms known in Parkinson's disease like bradykinesia [5]. Another pathological feature in Parkinson's disease is neural inclusion, in the form of so called Lewy bodies. Lewy body formation is believed to contribute to the neuronal degenerations, because at the site of those Lewy bodies neural damage can be found. The main protein forming those Lewy bodies is alpha-synuclein. In PD alpha-syn. can be found in 10% of the neurons in the substantia nigra. Research shows that this amount of alpha-syn. in the substantia nigra can be considered as cytotoxic and therefor this protein accumulation could contribute to the pathology of Parkinson's Disease [6].

Possible new cause Parkinson's Disease
Recently it has been discovered that in a very early stage of the disease lesions in the gastrointestinal tract arise before the occurrence of the abnormalities in substantia nigra [7]. The study done by Cersosimo et al. in 2013 shows that the symptoms in the GI tract like constipation occur before the motor-complains in 87% of all study participants. Additionally, Lewi bodies can not only be found in the central nervous system, they are also present in the intestinal enteric nerves [8]. This information all together leads to the newly formed hypothesis of Braak: ''α-syn. pathology starts in the submucosal plexus of the Enteric nervous system and propagates retrogradely to the CNS via vagal preganglionic axons of the dorsal motor neuron of the vagal nerve". Via the vagal nerve the pathology will spread; Originating in the guts towards areas in the brainstem including first the substantia nigra and afterwards also the basal forebrain and neocortex [7]. For toxins, pathogens and proteins like alpha-syn. to gain access to these nerves and promote oxidative stress, the intestinal barrier needs to be damaged and have an increase permeability. And indeed shown in the study done by Forshyth in 2011, the mucosa in PD patients shows damage and abnormal permeability [9].

Figure one: communication between the central and enteric nervous system takes place via the vagal nerve. Via the vagal nerve the pathology will spread via the dorsal motor neuron; Originating in the guts towards areas in the brainstem including first the substantia nigra and afterwards also the basal forebrain and neocortex [1].

Microbial dysbiosis in Parkinson's Disease
This, as mentioned above, suggest that the disease starts in the enteric nervous system and then spreads retrogradely towards the brainstem and the brain itself. But what in the gastrointestinal tract can contribute to the pathology in Parkinson's disease? Hasegawa et al. published a study in 2015 about intestinal microbial dysbiosis and a possible cause found in a decrease of serum lipopolysaccharide(LPS)-binding protein. They concluded there is more permeability to LPS without compromising the intestinal mucosa integrity in PD patients. This increased permeability may make PD patients more susceptible for dysbiosis in the microbiome [10]. However, it has never been proven which comes first. Researchers believe that it could be that in one patient the disease starts in the ENS and alpha-syn. moves retrogradely to the CNS and in another patient the other way around [1]. One way or another, intestinal microbial dysbiosis may be crucial in the development and progression of Parkinson's disease [10].

Want to read more about microbial dysbiosis in Parkinson's Disease? Then take a look at this article.

                                                                                                                                           Written by Jodie Dekker
                                                                                                                                                        Posted on 13 oct 2018

[1] Mulak, A et al. Brain-gut-microbiota axis in Parkinson's disease. World J Gastroenterol. 2015
Oct; 21(37). p.10609-10620.

[2] Parkinson's news today. Parkinson's Disease Statistics. Update date unknown. https://parkinsonsnewstoday.com/parkinsons-disease-statistics/ [Accessed 13-10-2018].

[3] Perez-Pardo P et al. The gut-brain axis in Parkinson's disease: Possibilities for food-based therapies. European Journal of Pharmacology. 2017 Dec; 817. P. 86-95.

[4] Edwards LL et al. Gastrointestinal dysfunction in Parkinson's disease: frequency and pathophysiology. Neurology. 1992 April; 42(4). P. 726-732.

[5] Bartels AL et al. Parkinson's Disease: The syndrome, the pathogenesis and pathophysiology. Cortex. 2009 sept; 45(8) p.915-921.

[6] Wakabayashi K et al. The Lewy body in Parkinson's disease: molecules implicated in the formation and degradation of alpha-synuclein aggregates. Neuropathology. 2007; 27 p. 494-506.

[7] Braak H et al. Gastric alpha-synuclein immunoreactive inclusions in Meissner's and Auerbach's plexuses in cases staged for Parkinson's disease-related brain pathology. Neurosci. Lett. 2006 March; 396(1). P 67-72.

[8] Cersosimo MG et al. Gastrointestinal manifestations in Parkinson's disease: prevalence and occurrence before symptoms. J. Neurol. 2013; 260. P. 1332-1338.

[9] Forsyth CB et al. Increased intestinal permeability correlates with sigmoid mucosa alpha-synuclein staining and endotoxin exposure markers in early Parkinson's disease. PLoS One. 2011; 6(12). e28032.

[10] Hasegawa S et al. Intestinal Dysbiosis and Lowered Serum Lipopolysaccharide-Binding Protein in Parkinson's Disease. PLoS One. 2015 Nov; 10(11). e0142164.