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      Microbial BMAA and the Pathway for Parkinson’s Disease Neurodegeneration

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          Abstract

          The neurotoxin β- N-methylamino-L-alanine (BMAA) is a natural non-proteinogenic diamino acid produced by several species of both prokaryotic (cyanobacteria) and eukaryotic (diatoms and dinoflagellates) microorganisms. BMAA has been shown to biomagnify through the food chain in some ecosystems, accumulating for example in seafood such as shellfish and fish, common dietary sources of BMAA whose ingestion may have possible neuronal consequences. In addition to its excitotoxic potential, BMAA has been implicated in protein misfolding and aggregation, inhibition of specific enzymes and neuroinflammation, all hallmark features of neurodegenerative diseases. However, the exact molecular mechanisms of neurotoxicity remain to be elucidated in detail. Although BMAA is commonly detected in its free form, complex BMAA-containing molecules have also been identified such as the paenilamicins, produced by an insect gut bacterial pathogen. On the other hand, production of BMAA or BMAA-containing molecules by members of the human gut microbiota, for example by non-photosynthetic cyanobacteria, the Melainabacteria, remains only hypothetical. In any case, should BMAA reach the gut it may interact with cells of the mucosal immune system and neurons of the enteric nervous system (ENS) and possibly target the mitochondria. Here, we review the available evidence and hint on possible mechanisms by which chronic exposure to dietary sources of this microbial neurotoxin may drive protein misfolding and mitochondrial dysfunction with concomitant activation of innate immune responses, chronic low-grade gut inflammation, and ultimately the neurodegenerative features observed across the gut-brain axis in Parkinson’s disease (PD).

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          Most cited references73

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          Inflammation in CNS neurodegenerative diseases

          Neurodegenerative diseases, the leading cause of morbidity and disability, are gaining increased attention as they impose a considerable socioeconomic impact, due in part to the ageing community. Neuronal damage is a pathological hallmark of Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, Huntington's disease, spinocerebellar ataxia and multiple sclerosis, although such damage is also observed following neurotropic viral infections, stroke, genetic white matter diseases and paraneoplastic disorders. Despite the different aetiologies, for example, infections, genetic mutations, trauma and protein aggregations, neuronal damage is frequently associated with chronic activation of an innate immune response in the CNS . The growing awareness that the immune system is inextricably involved in shaping the brain during development as well as mediating damage, but also regeneration and repair, has stimulated therapeutic approaches to modulate the immune system in neurodegenerative diseases. Here, we review the current understanding of how astrocytes and microglia, as well as neurons and oligodendrocytes, shape the neuroimmune response during development, and how aberrant responses that arise due to genetic or environmental triggers may predispose the CNS to neurodegenerative diseases. We discuss the known interactions between the peripheral immune system and the brain, and review the current concepts on how immune cells enter and leave the CNS . A better understanding of neuroimmune interactions during development and disease will be key to further manipulating these responses and the development of effective therapies to improve quality of life, and reduce the impact of neuroinflammatory and degenerative diseases.
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            Parkinson's disease: a dual‐hit hypothesis

            Accumulating evidence suggests that sporadic Parkinson's disease has a long prodromal period during which several non‐motor features develop, in particular, impairment of olfaction, vagal dysfunction and sleep disorder. Early sites of Lewy pathology are the olfactory bulb and enteric plexus of the stomach. We propose that a neurotropic pathogen, probably viral, enters the brain via two routes: (i) nasal, with anterograde progression into the temporal lobe; and (ii) gastric, secondary to swallowing of nasal secretions in saliva. These secretions might contain a neurotropic pathogen that, after penetration of the epithelial lining, could enter axons of the Meissner's plexus and, via transsynaptic transmission, reach the preganglionic parasympathetic motor neurones of the vagus nerve. This would allow retrograde transport into the medulla and, from here, into the pons and midbrain until the substantia nigra is reached and typical aspects of disease commence. Evidence for this theory from the perspective of olfactory and autonomic dysfunction is reviewed, and the possible routes of pathogenic invasion are considered. It is concluded that the most parsimonious explanation for the initial events of sporadic Parkinson's disease is pathogenic access to the brain through the stomach and nose – hence the term ‘dual‐hit’.
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              Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children.

              Children with autistic spectrum disorders (ASDs) tend to suffer from severe gastrointestinal problems. Such symptoms may be due to a disruption of the indigenous gut flora promoting the overgrowth of potentially pathogenic micro-organisms. The faecal flora of patients with ASDs was studied and compared with those of two control groups (healthy siblings and unrelated healthy children). Faecal bacterial populations were assessed through the use of a culture-independent technique, fluorescence in situ hybridization, using oligonucleotide probes targeting predominant components of the gut flora. The faecal flora of ASD patients contained a higher incidence of the Clostridium histolyticum group (Clostridium clusters I and II) of bacteria than that of healthy children. However, the non-autistic sibling group had an intermediate level of the C. histolyticum group, which was not significantly different from either of the other subject groups. Members of the C. histolyticum group are recognized toxin-producers and may contribute towards gut dysfunction, with their metabolic products also exerting systemic effects. Strategies to reduce clostridial population levels harboured by ASD patients or to improve their gut microflora profile through dietary modulation may help to alleviate gut disorders common in such patients.
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                Author and article information

                Contributors
                Journal
                Front Aging Neurosci
                Front Aging Neurosci
                Front. Aging Neurosci.
                Frontiers in Aging Neuroscience
                Frontiers Media S.A.
                1663-4365
                07 February 2020
                2020
                : 12
                : 26
                Affiliations
                [1] 1CNC–Center for Neuroscience and Cell Biology, University of Coimbra , Coimbra, Portugal
                [2] 2Ph.D. Programme in Biomedicine and Experimental Biology (PDBEB), Institute for Interdisciplinary Research, University of Coimbra , Coimbra, Portugal
                [3] 3Institute of Cellular and Molecular Biology, Faculty of Medicine, University of Coimbra , Coimbra, Portugal
                [4] 4Institute for Interdisciplinary Research (IIIUC), University of Coimbra , Coimbra, Portugal
                Author notes

                Edited by: Nicola Simola, University of Cagliari, Italy

                Reviewed by: Steven Robert Brenner, Saint Louis University, United States; Agata Copani, University of Catania, Italy

                *Correspondence: Sandra Morais Cardoso cardoso.sandra.m@ 123456gmail.com Nuno Empadinhas numenius@ 123456cnc.uc.pt
                Article
                10.3389/fnagi.2020.00026
                7019015
                32317956
                e246f76a-5703-460f-a53c-c1b9c9e30ca9
                Copyright © 2020 Nunes-Costa, Magalhães, G-Fernandes, Cardoso and Empadinhas.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 14 November 2019
                : 23 January 2020
                Page count
                Figures: 1, Tables: 0, Equations: 0, References: 110, Pages: 9, Words: 7857
                Funding
                Funded by: Fundação para a Ciência e a Tecnologia 10.13039/501100001871
                Funded by: European Regional Development Fund 10.13039/501100008530
                Categories
                Neuroscience
                Review

                Neurosciences
                parkinson’s disease,mitochondrial dysfunction,innate immunity,neurodegeneration,microbial β-n-methylamino-l-alanine (bmaa)

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