Urinary tract infections trigger synucleinopathy via the innate immune response

Symptoms in the urogenital organs are common in multiple system atrophy (MSA), also in the years preceding the MSA diagnosis. It is unknown how MSA is triggered and these observations in prodromal MSA led us to hypothesize that synucleinopathy could be triggered by infection of the genitourinary tract causing ɑ-synuclein (ɑSyn) to aggregate in peripheral nerves innervating these organs. As a first proof that peripheral infections could act as a trigger in MSA, this study focused on lower urinary tract infections (UTIs), given the relevance and high frequency of UTIs in prodromal MSA, although other types of infection might also be important triggers of MSA. We performed an epidemiological nested-case control study in the Danish population showing that UTIs are associated with future diagnosis of MSA several years after infection and that it impacts risk in both men and women. Bacterial infection of the urinary bladder triggers synucleinopathy in mice and we propose a novel role of ɑSyn in the innate immune system response to bacteria. Urinary tract infection with uropathogenic E. coli results in the de novo aggregation of ɑSyn during neutrophil infiltration. During the infection, ɑSyn is released extracellularly from neutrophils as part of their extracellular traps. Injection of MSA aggregates into the urinary bladder leads to motor deficits and propagation of ɑSyn pathology to the central nervous system in mice overexpressing oligodendroglial ɑSyn. Repeated UTIs lead to progressive development of synucleinopathy with oligodendroglial involvement in vivo. Our results link bacterial infections with synucleinopathy and show that a host response to environmental triggers can result in ɑSyn pathology that bears semblance to MSA

Inhibiting the mitochondrial pyruvate carrier does not ameliorate synucleinopathy in the absence of inflammation or metabolic deficits

Epidemiological studies suggest a link between type-2 diabetes and Parkinson’s disease (PD) risk. Treatment of type-2 diabetes with insulin sensitizing drugs lowers the risk of PD. We previously showed that the insulin sensitizing drug, MSDC-0160, ameliorates pathogenesis in some animal models of PD. MSDC-0160 reversibly binds the mitochondrial pyruvate carrier (MPC) protein complex, which has an anti-inflammatory effect and restores metabolic deficits. Since PD is characterized by the deposition of α-synuclein (αSyn), we hypothesized that inhibiting the MPC might directly inhibit αSyn aggregation in vivo in mammals. To answer if modulation of MPC can reduce the development of αSyn assemblies, and reduce neurodegeneration, we treated two chronic and progressive mouse models; a viral vector-based αSyn overexpressing model and a pre-formed fibril (PFF) αSyn seeding model with MSDC-0160. These two models present distinct types of αSyn pathology but lack inflammatory or autophagy deficits. Contrary to our hypothesis, we found that a modulation of MPC in these models did not reduce the accumulation of αSyn aggregates or mitigate neurotoxicity. Instead, MSDC-0160 changed the post-translational modification and aggregation features of αSyn. These results are consistent with the lack of a direct effect of MPC modulation on synuclein clearance in these models

a-synucleïne proteïne aggregatie in synucleinopathieën

Parkinson’s disease, dementia with Lewy Bodies and multiple system atrophy are age-related and devastating neurodegenerative disorders that are characterized by the presence of large proteinaceous clumps of the ɑ-synuclein protein scattered throughout the patient’s central nervous system. The identification of ɑ-synuclein in Lewy bodies made it clear that this protein has a central role in the etiopathogenesis of several age-related neurological diseases. However, today it is still unclear how ɑ-synuclein is involved in the neurodegenerative process and why patients, whose brains are scarred by deposits of a single peculiar protein, present with multiple clinical phenotypes, which we know today as the ‘synucleinopathies’. Recent studies have shown that ɑ-synuclein can misfold and self-associate into multimeric aggregated structural polymorphs of different sizes and shapes. These aggregated complexes have different biochemical and toxic properties, which has led to the identification of multiple ɑ-synuclein ‘strains’ and the hypothesis that strains could account for the clinical traits observed in synucleinopathy patients. In an experimental setting we have tested the ability of different ɑ-synuclein strains to induce pathology and show that strains are intrinsically pathogenic and have the capacity to induce different synucleinopathies. We furthermore show that pathogenic ɑ-synuclein can spread between connected brain regions and enter the central nervous system from the blood, which might further explain why synucleinopathies are characterized by a progressive disease course. Protein folding and misfolding is an intricate property of living systems. Understanding how ɑ-synuclein and other proteins misfold is still one of the biggest challenges in neurodegenerative research. This research is amongst the first to provide evidence that variations in the aggregation process of a single protein may be paralleled by the development of multiple neurological diseases. The discovery of strains not only helps us to understand why synucleinopathies are so different, it also holds great promise for our continuous search for new diagnostic tools and therapeutic strategies and raises optimism that someday we will be able to move from a symptomatic to a curative treatment.nrpages: 132status: publishe

Putting a strain on the brain: An update on synucleinopathy pathogenesis

Recent and exciting developments are providing new clues as to how different synucleinopathies such as Parkinson’s Disease (PD), Multiple System Atrophy (MSA) and neocortical Lewy Body Dementia (LBD) might originate

ɑ-Synuclein folds: the cards are on the table

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ɑ-Synuclein strains and seeding in Parkinson’s disease, incidental Lewy body disease, dementia with Lewy bodies and multiple system atrophy: similarities and differences

International audienceSeveral age-related neurodegenerative disorders are characterized by the deposition of aberrantly folded endogenous proteins. These proteins have prion-like propagation and amplification properties but so far appear nontransmissible between individuals. Because of the features they share with the prion protein, PrP, the characteristics of pathogenic protein aggregates in several progressive brain disorders, including different types of Lewy body diseases (LBDs), such as Parkinson's disease (PD), multiple system atrophy (MSA) and dementia with Lewy bodies (DLB), have been actively investigated. Even though the pleomorphic nature of these syndromes might suggest different underlying causes, ɑ-synuclein (ɑSyn) appears to play an important role in this heterogeneous group of diseases (the synucleinopathies). An attractive hypothesis is that different types of ɑSyn protein assemblies have a unique and causative role in distinct synucleinopathies. We will discuss the recent research progress on ɑSyn assemblies involved in PD, MSA and DLB; their behavior as strains; current spreading hypotheses; their ability to seed centrally and peripherally; and their implication for disease pathogenesis

Can infections trigger alpha-synucleinopathies?

As synucleinopathies, Parkinson's disease (PD) and multiple system atrophy (MSA) are neurodegenerative diseases that involve the spread of pathogenic alpha-synuclein (αSyn) throughout the brain. Recent studies have suggested a role for αSyn as an antimicrobial peptide in response to PD- and MSA-related infections of peripheral tissues, including those in the respiratory, gastrointestinal, and urogenital systems. In this chapter, we examine epidemiological and experimental evidence for a role of peripheral microbial infections in triggering alpha-synucleinopathies. We propose a model of how infectious triggers, in conjunction with inflammatory, environmental, and genetic facilitators, may result in transfer of pathogenic αSyn strains from the periphery to the brain, where they propagate and spread. Finally, we discuss future research challenges and programs necessary to clarify the role of infections as triggers of PD and MSA and, ultimately, to prevent the onset of these diseases by infectious triggers.status: publishe

Targeting energy metabolism via the mitochondrial pyruvate carrier as a novel approach to attenuate neurodegeneration

Several molecular pathways are currently being targeted in attempts to develop disease-modifying therapies to slow down neurodegeneration in Parkinson’s disease. Failure of cellular energy metabolism has long been implicated in sporadic Parkinson’s disease and recent research on rare inherited forms of Parkinson’s disease have added further weight to the importance of energy metabolism in the disease pathogenesis. There exists a new class of anti-diabetic insulin sensitizers in development that inhibit the mitochondrial pyruvate carrier (MPC), a protein which mediates the import of pyruvate across the inner membrane of mitochondria. Pharmacological inhibition of the MPC was recently found to be strongly neuroprotective in multiple neurotoxin-based and genetic models of neurodegeneration which are relevant to Parkinson’s disease. In this review, we summarize the neuroprotective effects of MPC inhibition and discuss the potential putative underlying mechanisms. These mechanisms involve augmentation of autophagy via attenuation of the activity of the mammalian target of rapamycin (mTOR) in neurons, as well as the inhibition of neuroinflammation, which is at least partly mediated by direct inhibition of MPC in glia cells. We conclude that MPC is a novel and potentially powerful therapeutic target that warrants further study in attempts to slow Parkinson’s disease progression

A web application to support the quantification and valuation of ecosystem services

Assessing the impacts of policies on a wide range of ecosystem services can support the development of cost-effective policies that establish win–win situations across different environmental domains. To explore the quantity and value of ecosystem services, the web-based application “nature value explorer” was developed. The application allows to estimate the impact of land use and land cover change on regulating and cultural ecosystem services in Flanders, Belgium. To ensure the applicability in day-to-day decision making as part of environmental impact assessments, user requirements were investigated prior to tool development. Finding the optimal balance between accuracy and complexity on the one hand and flexibility and user-friendliness on the other hand was an important challenge. To date, the nature value explorer has been successful in drawing the interest of policy makers and has been used several times to support decisions in infrastructure projects as well as in nature restoration projects in Flanders. This paper discusses the user requirements, the main tool characteristics, potential policy applications and future improvements. Three case studies illustrate the functionalities of the tool in day-to-day decision making