Intestinal infection triggers Parkinson’s disease-like symptoms in Pink1−/− mice

Matheoud, Diana; Cannon, Tyler; Voisin, Aurore; Penttinen, Anna‐Maija; Ramet, Lauriane; Fahmy, Ahmed; Ducrot, Charles; Laplante, Annie; Bourque, Marie‐Josée; Zhu, Lei; Cayrol, Romain; Campion, Armelle Le; McBride, Heidi M.; Gruenheid, Samantha; Trudeau, Louis-Éric; Desjardins, Michel

doi:10.1038/s41586-019-1405-y

Cited by 369 publications

(325 citation statements)

References 30 publications

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“…In line with these LPS-based studies and independent of PS, infections of the gut may precede Parkinson's disease (PD) by years or trigger it in an experimental mouse model (Matheoud, Cannon et al 2019, Nerius, Doblhammer et al 2019). The latter demonstrated involvement of glial cells in the pathogenesis of the autoimmune response resulting in a PD phenotype.…”

Section: Microglial Plasticity Due To Fetal and Neonatal Insults: A Mmentioning

confidence: 93%

Microglial memory of early life stress and inflammation: Susceptibility to neurodegeneration in adulthood

Desplats

Gutierrez

Antonelli

et al. 2020

Neuroscience & Biobehavioral Reviews

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We review evidence supporting the role of early life programming in the susceptibility for adult neurodegenerative diseases while highlighting questions and proposing avenues for future research to advance our understanding of this fundamental process. The key elements of this phenomenon are chronic stress, neuroinflammation triggering microglial polarization, microglial memory and their connection to neurodegeneration. We review the mediating mechanisms which may function as early biomarkers of increased susceptibility for neurodegeneration. Can we devise novel early life modifying interventions to steer developmental trajectories to their optimum?

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Section: Microglial Plasticity Due To Fetal and Neonatal Insults: A Mmentioning

confidence: 93%

Microglial memory of early life stress and inflammation: Susceptibility to neurodegeneration in adulthood

Desplats

Gutierrez

Antonelli

et al. 2020

Neuroscience & Biobehavioral Reviews

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“…61,62 It was also shown in a genetic model of PD (pink1 knock-out mice) that intestinal infection by pathogens elicits activation of cytotoxic T cells in the periphery and the brain and leads to deterioration of dopaminergic cells and motor impairment, suggesting that intestinal infection acts as a triggering event in PD. 63 Despite the increasing evidence linking the gut, a-synuclein, and inflammation to PD, there is no direct evidence that a pathogen is responsible for the pathology. Here, we present the first evidence from human samples indicating an overabundance of opportunistic pathogens in the gut microbiome of persons with PD.…”

Section: Opportunistic Pathogensmentioning

confidence: 99%

Characterizing dysbiosis of gut microbiome in PD: Evidence for overabundance of opportunistic pathogens

Wallen

Appah

Dean

et al. 2020

Preprint

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In Parkinson's disease (PD), gastrointestinal features are common and often precede the motor signs. Braak and colleagues proposed that PD may start in the gut, triggered by a pathogen, and spread to the brain. Numerous studies have examined the gut microbiome in PD, all found it to be altered, but found inconsistent results on associated microorganisms. Studies to date have been small (N=20 to 306) and are difficult to compare or combine due to varied methodology. We conducted a microbiome-wide association study (MWAS) with two large datasets for internal replication (N=333 and 507). We used uniform methodology when possible, interrogated confounders, and applied two statistical tests for concordance, followed by correlation network analysis to infer interactions. Fifteen genera were associated with PD at a microbiome-wide significance level, in both datasets, with both methods, with or without covariate adjustment. The associations were not independent, rather represented 3 clusters of co-occurring microorganisms. Cluster 1 was composed of opportunistic pathogens; all were elevated in PD. Cluster 2 were short-chain-fatty-acid producing bacteria; all were reduced in PD.Cluster 3 were carbohydrate-metabolizing probiotics; elevated in PD. Depletion of antiinflammatory short-chain-fatty-acid producing bacteria and elevated levels of probiotics are confirmatory. Overabundance of opportunistic pathogens is a novel finding and their identity provides a lead to experimentally test their role in PD. animal models. [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] Every study that has compared the global composition of the gut microbiome in PD vs. controls found it to be significantly altered; in contrast, attempts to identify PD-associated microorganisms have produced inconsistent results. 31,32 Low reproducibility has been attributed to small sample sizes (missing true associations due to low power), relaxed statistical thresholds (inflating false positive results), and publishing without a replication dataset (required for genomic studies). Differences in methods of DNA extraction, sequencing, bioinformatics and statistics can all contribute to inter-study variations. The choice of taxonomic resolution for analysis (PD has been tested at all levels from phylum to species) and the inconsistent taxonomic assignments and nomenclature used in various reference databases add to the confusion when comparing results. Last but not least, is confounding by heterogeneity in the populations that were studied: PD is heterogenous and so is the microbiome. PD subtypes cannot be readily identified thus patient populations are inevitably varied. A myriad of factors can affect the microbiome ranging from diet, health and medication to cultural habits, life-styles, race and geography. 33,34 Identifying microorganisms involved in the dysbiosis of the microbiome is essential for understanding their role in disease. We conducted a hypothesis-free microbiome-wide association study (MWAS) modeled after and usi...

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“…Early studies by Schurr and colleagues found that single-nucleotide polymorphisms (SNPs) in the PACRG-Parkin promoter region were strongly associated with leprosy [13]. Parkin and PINK1 have recently been implicated in mitochondria-dependent inflammation, in response to bacterial infection or mitochondrial stress [8][9][10]. Intriguingly, SNPs and missense variants in LRRK2, a gene associated with autosomal dominant PD, have also been linked to susceptibility, inflammatory responses and type-1 reactions in leprosy [12,45,46].…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, deletion of the parkin or pink1 genes in Drosophila results in mitochondrial defects that cause muscle degeneration [3][4][5]. While Parkin or PINK1 knockout (KO) mice do not exhibit significant muscle or neuronal degeneration on their own [6,7], mitochondrialinked stress and infection-induced inflammation can induce neurodegeneration in those strains [8][9][10]. Parkin KO mice are more susceptible to intracellular bacterial pathogens [11], and missense mutations in Parkin are associated with an increased susceptibility to a type-1 reaction in leprosy, a disease caused by a chronic Mycobacterium leprae infection [12].…”

Section: Introductionmentioning

confidence: 99%

Crystal structure of human PACRG in complex with MEIG1

Khan

Pelletier

Veyron

et al. 2019

Preprint

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In human, the Parkin Co-Regulated Gene (PACRG) shares a bidirectional promoter with Parkin, a gene involved in Parkinson's disease, mitochondrial quality control and inflammation. The PACRG protein is essential to the formation of the inner junction between doublet microtubules of the axoneme, a structure found in flagella and cilia. PACRG interacts with tubulin as well as the meiosis expressed gene 1 (MEIG1) protein, which is essential for spermiogenesis in mice.However, the 3D structure of human PACRG is unknown. Here, we report the crystal structure of the C-terminal domain of human PACRG in complex with MEIG1 at 2.1 Å resolution. PACRG adopts an a-helical structure with a loop insertion that mediates a conserved network of interactions with MEIG1. Using the cryo-electron tomography structure of the axonemal doublet microtubule from the flagellated protozoan Chlamydomonas reinhardtii, we generate a model of a mammalian microtubule doublet inner junction, which reveals how PACRG interacts with tubulin subunits in both the A-and B-tubules. Furthermore, the model shows that MEIG1 interacts with btubulin on the outer surface of the B-tubule, facing towards the central pair of the axoneme. We also model the PACRG-like protein (PACRGL), a homolog of PACRG with potential roles in microtubule remodelling and axonemal inner junction formation. Finally, we explore the evolution of the PACRG and Parkin head-to-head gene structure and analyze the tissue distribution of their transcripts. Our work establishes a framework to assess the function of the PACRG family of proteins and its adaptor proteins in the function of motile and non-motile cilia.We thank K. Winklhofer and J. Menschede for useful discussion that contributed to the development of this study. The beamline 08ID-1 at the Canadian

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Intestinal infection triggers Parkinson’s disease-like symptoms in Pink1−/− mice

Cited by 369 publications

References 30 publications

Microglial memory of early life stress and inflammation: Susceptibility to neurodegeneration in adulthood

Microglial memory of early life stress and inflammation: Susceptibility to neurodegeneration in adulthood

Characterizing dysbiosis of gut microbiome in PD: Evidence for overabundance of opportunistic pathogens

Crystal structure of human PACRG in complex with MEIG1

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