The gut‐brain axis is a hot topic in Parkinson's disease. In an attempt to decipher its role in the disease pathogenesis, several animal models have been developed. Most of these models tried to ...reproduce Braak's hypothesis by showing that the pathological process could spread from the gut to the brain (bottom‐up scenario). Interestingly, others groups showed that a top‐down scenario could also occur and that 6‐hydroxydopamine‐induced nigrostriatal denervation was sufficient to induce significant changes in the gastrointestinal tract. Aside from this toxic approach, the article by O’Donovan and colleagues in this edition of Neurogastroenterology and Motility showed that bilateral nigral injection of adeno‐associated virus (AAV)‐alpha‐synuclein in rats was accompanied by changes in the enteric nervous system and the gut microbiota, which occurred without any apparent brain‐to‐gut spread of human injected alpha‐synuclein. Some changes observed in the gastrointestinal tract of animals injected with AAV‐alpha‐synuclein were in line with previous observations in Parkinson's disease patients, including increased expression of glial markers, swollen tyrosine hydroxylase‐positive varicosities in the submucosal plexus, and decreases in Faecalibacterium and Lachnospiraceae. These findings suggest that, in addition to gut‐brain pathways, the brain‐to‐gut communication may also be involved in Parkinson's disease pathophysiology. In this mini‐review, we describe the strengths and limitations of the existing studies on the gut‐brain axis in experimental models of parkinsonism and discuss an alternative hypothesis in which the central and enteric nervous system would evolve separately during disease progression.
Enteric glial cells (EGCs) are in many respects similar to astrocytes of the central nervous system and express similar proteins including glial fibrillary acidic protein (GFAP). Changes in GFAP ...expression and/or phosphorylation have been reported during brain damage or central nervous system degeneration. As in Parkinson's disease (PD) the enteric neurons accumulate α‐synuclein, and thus are showing PD‐specific pathological features, we undertook the present survey to study whether the enteric glia in PD become reactive by assessing the expression and phosphorylation levels of GFAP in colonic biopsies. Twenty‐four PD, six progressive supranuclear palsy (PSP), six multiple system atrophy (MSA) patients, and 21 age‐matched healthy controls were included. The expression levels and the phosphorylation state of GFAP were analyzed in colonic biopsies by western blot. Additional experiments were performed using real‐time PCR for a more precise analysis of the GFAP isoforms expressed by EGCs. We showed that GFAPκ was the main isoform expressed in EGCs. As compared to control subjects, patients with PD, but not PSP and MSA, had significant higher GFAP expression levels in their colonic biopsies. The phosphorylation level of GFAP at serine 13 was significantly lower in PD patients compared to control subjects. By contrast, no change in GFAP phosphorylation was observed between PSP, MSA and controls. Our findings provide evidence that enteric glial reaction occurs in PD and further reinforce the role of the enteric nervous system in the initiation and/or the progression of the disease.
We showed that GFAP is over‐expressed and hypophosphorylated in the enteric glial cells (EGCs) of Parkinson's disease (PD) patients as compared to healthy subjects and patients with atypical parkinsonism (MSA, multiple system atrophy and PSP, progressive supranuclear palsy). Our findings provide evidence that enteric glial reaction occurs in PD but not in PSP and MSA and further reinforce the role of the enteric nervous system in the pathophysiology of PD.
We showed that GFAP is over‐expressed and hypophosphorylated in the enteric glial cells (EGCs) of Parkinson's disease (PD) patients as compared to healthy subjects and patients with atypical parkinsonism (MSA, multiple system atrophy and PSP, progressive supranuclear palsy). Our findings provide evidence that enteric glial reaction occurs in PD but not in PSP and MSA and further reinforce the role of the enteric nervous system in the pathophysiology of PD.
Read the Editorial Highlight for this article on page 729.
While the pathogenesis of Parkinson’s disease is not fully understood, there is increasing evidence that inflammatory responses in the brain are implicated in both disease initiation and progression. ...The inflammatory process in Parkinson’s disease is, however, not limited to the brain but also involves the gastrointestinal tract. High amounts of cytokines and inflammatory markers are found in the colon of Parkinson’s disease patients and there is now strong epidemiological and genetical evidence linking Parkinson’s disease to inflammatory bowel diseases. Recent findings obtained in both experimental inflammatory bowel diseases and Parkinson’s disease further support a bidirectional link between gastrointestinal inflammation and brain neurodegeneration. Altogether, these observations suggest a role for gastrointestinal inflammation in the initiation and progression of Parkinson’s disease.
Lewy bodies and neurites, the pathological signatures found in the central nervous system of Parkinson's disease (PD) patients, are primarily composed of aggregated alpha-synuclein (aSyn). The ...observation that aSyn aggregates are also found in the enteric nervous system has prompted several studies aimed at developing a diagnostic procedure based on the detection of pathological aSyn in gastrointestinal (GI) biopsies. The existing studies, which have all used immunohistochemistry for the detection of pathological aSyn, have had conflicting results. In the current survey, we analyzed the seeding propensity of aSyn aggregates from GI biopsies.
A total of 29 subjects participated to this study, 18 PD patients and 11 controls. For each patient, 2 to 4 GI biopsies were taken from the same site (antrum, sigmoid colon or rectum) and used to seed the aggregation of recombinant aSyn in an assay inspired from the protein misfolding cyclic amplification (PMCA) method. In a subset of patients and controls (14 and 3, respectively), one or two additional biopsies were analyzed by immunohistochemistry for the presence of phosphorylated aSyn histopathology (PASH) using antibodies against phosphorylated aSyn and PGP 9.5.
Except for one subject, none of the control samples seeded aSyn aggregation in PMCA reaction. GI biopsies from patients with PD seeded aSyn aggregation in 10 out of 18 cases (7 from the sigmoid colon, 2 from the antrum and one from the rectum). There was good agreement between PMCA and immunohistochemistry results as, except for two cases, all PMCA-positive PD patients were also PASH-positive.
Our findings show that the PMCA method we implemented is capable of detecting aSyn aggregates in routine GI biopsies. They also suggest that rectum biopsies do not contain sufficient amounts of aggregated aSyn to detect seeded assembly by PMCA. While encouraging, our findings indicate that further studies are needed to establish the diagnostic potential of the PMCA method we implemented to detect aSyn aggregates in upper GI biopsies.
•Protein Misfolding Cyclic Amplification (PMCA) method to assess PD in GI biopsies.•GI biopsies seed aSYN aggregation in PMCA reaction.•10 out of 18 PD cases were found positive by PMCA, only 1 out of 11 controls.•Antrum or sigmoid colon biopsies are the most suited for PMCA-based PD diagnosis.
It is now well established that Parkinson's disease (PD) is not only a movement disorder of the CNS but also a gastrointestinal disorder affecting the enteric nervous system (ENS). The gut-brain axis ...is a bidirectional communication between the brain and the gastrointestinal tract, which comprises besides the CNS and the ENS, the intestinal epithelial barrier, the intestinal microbiota and the enteroendocrine systems. In this review, we present the clinical and pathological evidence suggesting that the gut-brain axis is dysfunctional in PD by discussing the possible role of gut microbiota, inflammation and permeability in the development of the disease.
Does Parkinson’s disease start in the gut? Lionnet, Arthur; Leclair-Visonneau, Laurène; Neunlist, Michel ...
Acta neuropathologica,
2018/1, Letnik:
135, Številka:
1
Journal Article
Recenzirano
Parkinson’s disease (PD) is pathologically characterized by the presence of intraneuronal inclusions, termed Lewy bodies and Lewy neurites, whose main component is alpha-synuclein. Based on the ...topographic distribution of Lewy bodies and neurites established after autopsy from PD patients, Braak and coworkers hypothesized that PD pathology may start in the gastrointestinal tract then spread through the vagus nerve to the brain. This hypothesis has been reinforced by the discovery that alpha-synuclein may be capable of spreading transcellularly, thereby providing a mechanistic basis for Braak’s hypothesis. This ‘gut to brain’ scenario has ignited heated debates within the movement disorders community and prompted a large number of studies in both humans and animals. Here, we review the arguments for and against the gut as the origin of PD. We conclude that the human autopsy evidence does not support the hypothesis and that it is too early to draw any definitive conclusions. We discuss how this issue might be further addressed in future research.
Background
It is now well established that phosphorylated alpha‐synuclein histopathology, the pathologic hallmark of Parkinson's disease (PD) is not limited to the brain but also extends to the ...enteric nervous system (ENS). This observation led to the hypothesis that the ENS could play a pivotal role in the development of PD. Research on the enteric synucleinopathy has, however, been hampered by difficulties in detecting phosphorylated alpha‐synuclein in the ENS by Western blotting, even when the transferred membrane is fixed with an optimized protocol. This suggests that the available antibodies used in previous studies lacked of sensitivity for the detection of phosphorylated alpha‐synuclein at Ser129 in enteric neurons. Here, we evaluated three recent commercially available phospho‐alpha‐synuclein antibodies and compared them to two antibodies used in previous research.
Methods
The specificity and sensitivity of the 5 antibodies were evaluated by Western blot performed with recombinant alpha‐synuclein and with protein lysates from rat primary cultures of ENS. In primary culture of ENS, additional experiments were performed with the most specific antibody in order to modulate alpha‐synuclein phosphorylation and to validate its utilization in immunofluorescence experiments.
Results
The rabbit monoclonal antibody D1R1R uniquely and robustly detected endogenous phosphorylated alpha‐synuclein at Ser129 in rat primary culture of ENS without any non‐specific bands, allowing for a reliable analysis of phosphorylated alpha‐synuclein regulation by pharmacologic means.
Conclusions and inferences
Using D1R1R antibody together with the optimized protocol for membrane fixation may help deciphering the signaling pathways involved in enteric alpha‐synuclein post‐translational regulation in PD.
The rabbit monoclonal D1R1R antibody specifically detects endogenous alpha‐synuclein phosphorylated at Ser129 in rat primary culture of ENS in Western blot. This antibody also works for immunofluorescence experiments. The D1R1R antibody may help deciphering the signaling pathways involved in the regulation of enteric alpha‐synuclein phosphorylation in Parkinson's disease. Scale bar is 100 µm.
Don't get confused, there is no typo nor editing mistake in the title of this Editorial as ‘Skin biopSYN’ stands for ‘detection of alpha-synuclein in skin biopsies’. Skin has become a hot topic in ...Parkinson's disease (PD) and there has been an exponential growth research over recent years. Following the observation that Lewy bodies and neurites from the brain of sporadic PD patients were highly immunoreactive for alpha-synuclein, alpha and phospho-alpha-synuclein immunohistochemical staining quickly became the method of choice for the neuropathological diagnosis of PD 1,2. Using this approach, several neuropathology laboratories demonstrated that phospho-alpha-synuclein histopathology (PASH) is not limited to the brain but also widespread throughout the peripheral autonomic networks 3, including the autonomic innervation of the skin 4. This is of particular interest because the development of biomarkers for PD has been hampered by the fact that the core pathology lies in the brainstem, deeply buried and hidden from direct study in living patients. In this context, the accessibility of the skin with routine punch biopsies makes it a perfect candidate for the development of original histopathological markers that will directly evaluate the pathological process in PD 5. This logically led several groups to study if immunohistochemical investigation for PASH in the biopsied skin may be a useful tool for the premortem diagnosis of PD. In the first paper on the topic, published in 2010, only 2 out of 20 parkinsonian patients were PASH + when skin punch biopsies of the chest were analyzed 6 (Fig. 1). It was not until 2014 that two independent groups convincingly showed that skin biopsies (performed at multiple sites and with optimized staining protocols) allowed to detect PASH and to discriminate between PD and controls with an acceptable sensitivity and an excellent specificity 7,8 (Fig. 1). The saga of skin biopsies as a potential histopathological marker for PD was launched and since then more than 30 studies on this subject have been published (reviewed in Ref. 9).
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