The relation between α-synuclein and microglia in Parkinson’s disease: Recent developments

Sanchez-Guajardo, Vanesa; Tentillier, Noemie; Romero‐Ramos, Marina

doi:10.1016/j.neuroscience.2015.02.008

Cited by 157 publications

(125 citation statements)

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“…Colonic biopsies from PD patients indeed showed enhanced pro-inflammatory cytokines and glial markers correlating with disease progression [62, 63]. Furthermore, there is evidence of α-syn contributing to neuro-inflammation by potentiating microglial or astroglial activation [64].…”

Section: Discussionmentioning

confidence: 99%

Functional implications of microbial and viral gut metagenome changes in early stage L-DOPA-naïve Parkinson’s disease patients

et al. 2017

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BackgroundParkinson’s disease (PD) presently is conceptualized as a protein aggregation disease in which pathology involves both the enteric and the central nervous system, possibly spreading from one to another via the vagus nerves. As gastrointestinal dysfunction often precedes or parallels motor symptoms, the enteric system with its vast diversity of microorganisms may be involved in PD pathogenesis. Alterations in the enteric microbial taxonomic level of L-DOPA-naïve PD patients might also serve as a biomarker.MethodsWe performed metagenomic shotgun analyses and compared the fecal microbiomes of 31 early stage, L-DOPA-naïve PD patients to 28 age-matched controls.ResultsWe found increased Verrucomicrobiaceae (Akkermansia muciniphila) and unclassified Firmicutes, whereas Prevotellaceae (Prevotella copri) and Erysipelotrichaceae (Eubacterium biforme) were markedly lowered in PD samples. The observed differences could reliably separate PD from control with a ROC-AUC of 0.84. Functional analyses of the metagenomes revealed differences in microbiota metabolism in PD involving the ẞ-glucuronate and tryptophan metabolism. While the abundances of prophages and plasmids did not differ between PD and controls, total virus abundance was decreased in PD participants. Based on our analyses, the intake of either a MAO inhibitor, amantadine, or a dopamine agonist (which in summary relates to 90% of PD patients) had no overall influence on taxa abundance or microbial functions.ConclusionsOur data revealed differences of colonic microbiota and of microbiota metabolism between PD patients and controls at an unprecedented detail not achievable through 16S sequencing. The findings point to a yet unappreciated aspect of PD, possibly involving the intestinal barrier function and immune function in PD patients. The influence of the parkinsonian medication should be further investigated in the future in larger cohorts.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-017-0428-y) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Functional implications of microbial and viral gut metagenome changes in early stage L-DOPA-naïve Parkinson’s disease patients

et al. 2017

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“…Moreover, although none of the SCFA metabolism pathways per se were significant, some of their key components were; e.g., butyrate kinase (KEGG_K00929) which catalyzes a reversible reaction between butyrate and butanoyl-phosphate 38 was reduced in PD (FDR=0.04), and acetyl-CoA synthetase (KEGG_K01895) which converts acetate to acetyl-CoA 39 was elevated (FDR=3E-3). SCFA deficiency is an attractive hypothesis for PD because it could potentially explain inflammation and microglial activation in the brain 10, 40, 41 , and gastrointestinal features of the disease (leaky gut, 4, 42 constipation 1, 43 and colonic inflammation 3, 44, 45 ), but it is not the whole picture. There is sufficient evidence to speculate that, on one extreme, shortage of SCFA may be at the root of PD, and that replenishing the microbiome with SCFA-producing bacteria may prevent PD and reverse the disease in those who are affected.…”

Section: Discussionmentioning

confidence: 99%

Parkinson's disease and Parkinson's disease medications have distinct signatures of the gut microbiome

et al. 2017

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Background There is mounting evidence for a connection between the gut and Parkinson’s disease (PD). Dysbiosis of gut microbiota could explain several features of PD. Objective To determine if PD involves dysbiosis of gut microbiome, disentangle effects of confounders, and identify candidate taxa and functional pathways to guide research. Methods 197 PD cases and 130 controls were studied. Microbial composition was determined by 16S rRNA gene sequencing of DNA extracted from stool. Metadata were collected on 39 potential confounders including medications, diet, gastrointestinal symptoms, and demographics. Statistical analyses were conducted while controlling for potential confounders and correcting for multiple testing. We tested differences in the overall microbial composition, taxa abundance, and functional pathways. Results Independent microbial signatures were detected for PD (P=4E-5), subjects’ region of residence within the United States (P=3E-3), age (P=0.03), sex (P=1E-3) and dietary fruits/vegetables (P=0.01). Among patients, independent signals were detected for catechol-O-methyltransferase-inhibitors (P=4E-4), anticholinergics (P=5E-3), and possibly carbidopa/levodopa (P=0.05). We found significantly altered abundance of Bifidobacteriaceae, Christensenellaceae, [Tissierellaceae], Lachnospiraceae, Lactobacillaceae, Pasteurellaceae and Verrucomicrobiaceae families. Functional predictions revealed changes in numerous pathways including metabolism of plant-derived compounds and xenobiotics degradation. Conclusion PD is accompanied by dysbiosis of gut microbiome. Results coalesce divergent findings of prior studies, reveal altered abundance of several taxa, nominate functional pathways, and demonstrate independent effects of PD medications on the microbiome. The findings provide new leads and testable hypotheses on the pathophysiology and treatment of PD.

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“…Also proteins like alpha‐synuclein (α‐synuclein), which has long been implicated in the pathogenesis of PD (Polymeropoulos et al, 1997) could act as both modulators of glial functions and as antigens themselves activating the peripheral and central immune system (Harms et al, 2013; Reynolds et al, 2008; Sanchez‐Guajardo et al, 2015). Thus in PD itself, α‐synuclein itself might be an antigen used by MHC II during antigen presentation and thus leading to the observed glial infiltration in PD (Hunot and Hirsch, 2003).…”

Section: Discussionmentioning

confidence: 99%

Evidence for a role of adaptive immune response in the disease pathogenesis of theMPTPmouse model of Parkinson's disease

Martin

Santoro

Mustafa

et al. 2015

Glia

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Parkinson's disease (PD) is the second most common neurodegenerative disease and results from the loss of dopaminergic neurons of the nigrostriatal pathway. The pathogenesis of PD is poorly understood, but inflammatory processes have been implicated. Indeed increases in the number of major histocompatibility complex II (MHC II) reactive cells have long been recognised in the brains of PD patients at post‐mortem. However whether cells expressing MHC II play an active role in PD pathogenesis has not been delineated. This was addressed utilising a transgenic mouse null for MHC II and the parkinsonian toxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP). In wild‐type mice MHC II levels in the ventral midbrain were upregulated 1–2 days after MPTP treatment and MHC II was localized in both astrocytes and microglia. MHC II null mice showed significant reductions in MPTP‐induced dopaminergic neuron loss and a significantly reduced invasion of astrocytes and microglia in MHC II null mice receiving MPTP compared with controls. In addition, MHC II null mice failed to show increases in interferon‐γ or tumour necrosis factor‐α in the brain after MPTP treatment, as was found in wild‐type mice. However, interleukin‐1β was significantly increased in both wild‐type and MHC II null mice. These data indicate that in addition to microglial cell/myeloid cell activation MHC Class II‐mediated T cell activation is required for the full expression of pathology in this model of PD. GLIA 2016;64:386–395

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The relation between α-synuclein and microglia in Parkinson’s disease: Recent developments

Cited by 157 publications

References 131 publications

Functional implications of microbial and viral gut metagenome changes in early stage L-DOPA-naïve Parkinson’s disease patients

Functional implications of microbial and viral gut metagenome changes in early stage L-DOPA-naïve Parkinson’s disease patients

Parkinson's disease and Parkinson's disease medications have distinct signatures of the gut microbiome

Evidence for a role of adaptive immune response in the disease pathogenesis of theMPTPmouse model of Parkinson's disease

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