Microbial BMAA and the Pathway for Parkinson’s Disease Neurodegeneration

Nunes-Costa, Daniela; Magalhães, João Duarte; G-Fernandes, Maria; Cardoso, Sandra M.; Empadinhas, Nuno

doi:10.3389/fnagi.2020.00026

Cited by 62 publications

(46 citation statements)

References 110 publications

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“…Phylum Cyanobacteria is a bacteria presumably to be involved in the onset of neurodegenerative disease such as Parkinson disease. Cyanobacteria produces neurotoxin b-N-methylamino-L-alanine that may trigger neurodegeneration by promoting mitochondrial dysfunction, protein misfolding, and innate immune responses in genetically susceptible individuals [ 41 ]. This phylum was observed to relatively increase in aged mice, and the associated gut dysbiosis was also observed in two different mouse models of progeria where fecal microbiota transplantation from wild-type mice enhanced their lifespan and health [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Association between aging-dependent gut microbiome dysbiosis and dry eye severity in C57BL/6 male mouse model: a pilot study

et al. 2021

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Background While aging is a potent risk factor of dry eye disease, age-related gut dysbiosis is associated with inflammation and chronic geriatric diseases. Emerging evidence have demonstrated that gut dysbiosis contributes to the pathophysiology or exacerbation of ocular diseases including dry eye disease. However, the relationship between aging-related changes in gut microbiota and dry eye disease has not been elucidated. In this pilot study, we investigated the association between aging-dependent microbiome changes and dry eye severity in C57BL/6 male mice. Results Eight-week-old (8 W, n = 15), one-year-old (1Y, n = 10), and two-year-old (2Y, n = 8) C57BL/6 male mice were used. Dry eye severity was assessed by corneal staining scores and tear secretion. Bacterial genomic 16 s rRNA from feces was analyzed. Main outcomes were microbiome compositional differences among the groups and their correlation to dry eye severity. In aged mice (1Y and 2Y), corneal staining increased and tear secretion decreased with statistical significance. Gut microbiome α-diversity was not different among the groups. However, β-diversity was significantly different among the groups. In univariate analysis, phylum Firmicutes, Proteobacteria, and Cyanobacteria, Firmicutes/Bacteroidetes ratio, and genus Alistipes, Bacteroides, Prevotella, Paraprevotella, and Helicobacter were significantly related to dry eye severity. After adjustment of age, multivariate analysis revealed phylum Proteobacteria, Firmicutes/Bacteroidetes ratio, and genus Lactobacillus, Alistipes, Prevotella, Paraprevotella, and Helicobacter to be significantly associated with dry eye severity. Conclusions Our pilot study suggests that aging-dependent changes in microbiome composition are related to severity of dry eye signs in C57BL/6 male mice.

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Section: Discussionmentioning

confidence: 99%

Association between aging-dependent gut microbiome dysbiosis and dry eye severity in C57BL/6 male mouse model: a pilot study

et al. 2021

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“…Recently, a novel class of non-photosynthetic cyanobacteria designated Melainabacteria was identified in tap and groundwater as well as in the human gut [ 58 ]. This newly identified group of bacteria may be a candidate for BMAA production within the gut, as a putative strategy to cope with the competitive pressure in such an overpopulated environment, a mechanism that was probably retained during evolution [ 59 ]. Although BMAA has been characterized as a non-proteinogenic amino acid that can be misincorporated into proteins [ 30 ] causing endoplasmic reticulum stress, redox imbalance, and caspase-dependent apoptotic cell death [ 31 ], we present evidence for its direct action on mitochondria.…”

Section: Discussionmentioning

confidence: 99%

Microbial BMAA elicits mitochondrial dysfunction, innate immunity activation, and Alzheimer’s disease features in cortical neurons

Silva

Candeias

Esteves

et al. 2020

J Neuroinflammation

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Background After decades of research recognizing it as a complex multifactorial disorder, sporadic Alzheimer’s disease (sAD) still has no known etiology. Adding to the myriad of different pathways involved, bacterial neurotoxins are assuming greater importance in the etiology and/or progression of sAD. β-N-Methylamino-l-alanine (BMAA), a neurotoxin produced by some microorganisms namely cyanobacteria, was previously detected in the brains of AD patients. Indeed, the consumption of BMAA-enriched foods has been proposed to induce amyotrophic lateral sclerosis-parkinsonism-dementia complex (ALS-PDC), which implicated this microbial metabolite in neurodegeneration mechanisms. Methods Freshly isolated mitochondria from C57BL/6 mice were treated with BMAA and O2 consumption rates were determined. O2 consumption and glycolysis rates were also measured in mouse primary cortical neuronal cultures. Further, mitochondrial membrane potential and ROS production were evaluated by fluorimetry and the integrity of mitochondrial network was examined by immunofluorescence. Finally, the ability of BMAA to activate neuronal innate immunity was quantified by addressing TLRs (Toll-like receptors) expression, p65 NF-κB translocation into the nucleus, increased expression of NLRP3 (Nod-like receptor 3), and pro-IL-1β. Caspase-1 activity was evaluated using a colorimetric substrate and mature IL-1β levels were also determined by ELISA. Results Treatment with BMAA reduced O2 consumption rates in both isolated mitochondria and in primary cortical cultures, with additional reduced glycolytic rates, decrease mitochondrial potential and increased ROS production. The mitochondrial network was found to be fragmented, which resulted in cardiolipin exposure that stimulated inflammasome NLRP3, reinforced by decreased mitochondrial turnover, as indicated by increased p62 levels. BMAA treatment also activated neuronal extracellular TLR4 and intracellular TLR3, inducing p65 NF-κB translocation into the nucleus and activating the transcription of NLRP3 and pro-IL-1β. Increased caspase-1 activity resulted in elevated levels of mature IL-1β. These alterations in mitochondrial metabolism and inflammation increased Tau phosphorylation and Aβ peptides production, two hallmarks of AD. Conclusions Here we propose a unifying mechanism for AD neurodegeneration in which a microbial toxin can induce mitochondrial dysfunction and activate neuronal innate immunity, which ultimately results in Tau and Aβ pathology. Our data show that neurons, alone, can mount inflammatory responses, a role previously attributed exclusively to glial cells.

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“…Human contact with aerosol or waterborne toxins can also have other minor deleterious impacts, such as dermatological or respiratory irritation [58]. Moreover, there is increasing epidemiological evidence of relationships between environmental toxins and neurodegenerative diseases, including ALS, AD, and PD [27,59,60].…”

Section: Heavy Metalsmentioning

confidence: 99%

Cyanobacteria, Cyanotoxins, and Neurodegenerative Diseases: Dangerous Liaisons

Sini

Dang

Fais

et al. 2021

IJMS

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The prevalence of neurodegenerative disease (ND) is increasing, partly owing to extensions in lifespan, with a larger percentage of members living to an older age, but the ND aetiology and pathogenesis are not fully understood, and effective treatments are still lacking. Neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis are generally thought to progress as a consequence of genetic susceptibility and environmental influences. Up to now, several environmental triggers have been associated with NDs, and recent studies suggest that some cyanotoxins, produced by cyanobacteria and acting through a variety of molecular mechanisms, are highly neurotoxic, although their roles in neuropathy and particularly in NDs are still controversial. In this review, we summarize the most relevant and recent evidence that points at cyanotoxins as environmental triggers in NDs development.

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Microbial BMAA and the Pathway for Parkinson’s Disease Neurodegeneration

Cited by 62 publications

References 110 publications

Association between aging-dependent gut microbiome dysbiosis and dry eye severity in C57BL/6 male mouse model: a pilot study

Association between aging-dependent gut microbiome dysbiosis and dry eye severity in C57BL/6 male mouse model: a pilot study

Microbial BMAA elicits mitochondrial dysfunction, innate immunity activation, and Alzheimer’s disease features in cortical neurons

Cyanobacteria, Cyanotoxins, and Neurodegenerative Diseases: Dangerous Liaisons

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