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Symposium 3_2: Gut-brain axis in Parkinson’s Disease: from animal models to patients
Time:
Friday, 15/Sept/2023:
11:30am - 12:45pm
Session Chair: Vanessa Porrini, University of Brescia Session Chair: Giovanna Gambarotta, University of Torino
Location:Sala Londra
210 seats
Under 40 Symposium
Session Abstract
Prodromal constipation and early intestinal α-synuclein deposition have suggested the role of α-synuclein gut-to-brain propagation in Parkinson’s disease (PD) onset. New perspectives about the translational potential of these topics will be addressed in the present symposium. First, we will point out the mechanism by which α-synuclein impairs intestinal epithelial barrier and the involvement of vagal nerve in gut-to-brain α-synuclein spreading in PD mouse models. Next, we will consider the impact of constipation on PD progression in de novo patients. Finally, this symposium will provide new insights on the role of gut as a target for early therapeutic interventions in PD.
Presentations
11:30am - 11:55am
Prodromal intestinal symptoms in Parkinson’s disease: evidence from preclinical models
Vanessa D'Antongiovanni
University of Pisa, Italy
Gastrointestinal dysfunctions can affect Parkinson's disease (PD) patients long before the onset of motor symptoms. Several lines of evidence suggest that enteric accumulation of α-synuclein (αS) inclusions (a hallmark of PD) and colonic inflammation could contribute to bowel motor abnormalities since the earliest stages of PD. However, current knowledge does not allow to establish a clear relationship between altered mucosal permeability, enteric inflammation, bowel dysmotility and PD pathology. Based on this background, the present lecture is to provide an integrated overview of the experimental evidence about the relevance of intestinal symptoms in PD. Special attention will be paid to discuss current scientific evidence on the molecular mechanisms underlying the interplay between early αS accumulation, mucosal permeability, bowel inflammation and colonic motor activity in pre-clinical models of PD, before onset of central neurodegeneration.
11:55am - 12:20pm
Gut-to-brain progression of synucleinopathy in the c-rel-/- mouse model of Parkinson's disease
Department of Molecular and Translational Medicine, University of Brescia, Italy
Objective. A growing body of evidence links Parkinson's disease (PD) to the gastrointestinal tract. Braak and colleagues proposed that PD pathology starts from the intestine and end to the brain. According to this theory, the vagal nerve plays a crucial role in gut-to-brain propagation of alpha-synuclein (AS) pathology. The resection of gastric vagal nerve (vagotomy) decreases PD pathology in animal models. Finally, epidemiological studies show that vagotomy is associated with a decreased risk for PD in humans. NF-κB/c-Rel deficient (c-rel-/-) mice develop a progressive PD-like phenotype, presenting both prodromal and motor symptoms as well as nigrostriatal dopaminergic neurons degeneration and progressive caudo-rostral brain deposition of AS.
Aims of this study were: 1) the characterization of intestinal pathology and 2) the role of vagal nerve in the gut-to-brain spreading of AS, by assessing monolateral vagotomy (hemivagotomy), in c-rel-/- mice.
Results. At intestinal level, accumulation of phosphorylated AS was present in the myenteric plexus of c-rel-/- mice proximal colon at 2 months and increased at 10 months. Gut synucleinopathy was paralleled by increasing oxidative stress and inflammation markers in 10-month-old c-rel-/-mice. Moreover, AS deposition was prevented in the ipsilateral side of the dorsal motor nucleus of the vagus in hemivagotomized c-rel-/- mice at 12 months of age.
Conclusions. These results indicate that the c-rel-/- mice develop a progressive PD pathology at intestinal levels. Furthermore, the vagal nerve can partecipate to the gut-to brain spreading of AS in this PD mouse model. This study aims to characterize 1) the intestinal pathology and 2) the role of vagal nerve in the gut-to-brain spreading of AS, by assessing monolateral vagotomy (hemivagotomy), in c-rel-/- mice.
12:20pm - 12:45pm
Impact of constipation on clinical-biochemical profile of De Novo Parkinson's Disease
Piergiorgio Grillo
Neurology Unit, Department of Systems Medicine, University of Rome "Tor Vergata" Rome, Italy; Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy
Constipation is one of the most frequent non motor disturbances in Parkinson’s Disease (PD) that basically reflects the involvement of the enteric nervous system in neurodegeneration. The impact of slow intestinal transit on quality of life of PD subjects has been widely demonstrated. Gut disturbances are indeed cause of discomfort, predispose to several complications and increase the risk of motor fluctuations by altering the pharmacokinetics of levodopa.
According to multiple studies, the presence of impaired gastrointestinal motility, especially when occurring in the premotor phase of PD, might identify a subgroup of PD subjects with peculiar clinical-biological features and specific neurodegenerative trajectories. Moreover, the analysis of CSF, blood and olfactory mucosa biomarkers in PD patients with constipation disclosed the prominent systemic inflammation as a characterizing trait.
Here, we will recapitulate evidence indicating that constipation, regardless of its action on levodopa absorption, might profile a PD subtype clinically frailer, fitting in the so-called “body-first pathogenic hypothesis”, a model of ascending neurodegeneration from gut to brain opposite to “brain-first”. In addition, we will summarize clinical and preclinical evidence, suggesting that a proper management of gastrointestinal motility with probiotics could be an effective therapeutic strategy for PD, via the modulation of molecular and cellular mechanisms linked to neurodegeneration.
