Maladie cœliaque | EPFL Graph Search

La maladie cœliaque (pron. ), aussi appelée entéropathie au gluten, cœliaquie ou intolérance au gluten, est une maladie auto-immune, caractérisée par une atrophie villositaire (destruction de la paroi de l'intestin grêle). Cette maladie est une intolérance permanente à différentes fractions protéiques du gluten contenues dans différents types de céréales telles que le blé (froment), l'orge ou le seigle. Il en résulte une malabsorption de certains nutriments (vitamines, fer, calcium…), donc des carences alimentaires. Les personnes atteintes doivent suivre un régime strict sans gluten à vie. Aujourd'hui, aucun traitement médicamenteux n’existe. La maladie cœliaque ne doit pas être confondue avec l'allergie au gluten, qui est une allergie alimentaire, ni avec la sensibilité non cœliaque au gluten, une entité controversée. Historique Approche clinique La première description moderne et détaillée de la maladie a été faite en 1888, par un médecin pédiatre du St Bar

Opportunities and challenges of alpha-synuclein as a potential biomarker for Parkinson's disease and other synucleinopathies

Hilal Lashuel, Pedro José Santana Ribeiro Magalhães

Parkinson's disease (PD), the second most common progressive neurodegenerative disease, develops and progresses for 10-15 years before the clinical diagnostic symptoms of the disease are manifested. Furthermore, several aspects of PD pathology overlap with other neurodegenerative diseases (NDDs) linked to alpha-synuclein (aSyn) aggregation, also called synucleinopathies. Therefore, there is an urgent need to discover and validate early diagnostic and prognostic markers that reflect disease pathophysiology, progression, severity, and potential differences in disease mechanisms between PD and other NDDs. The close association between aSyn and the development of pathology in synucleinopathies, along with the identification of aSyn species in biological fluids, has led to increasing interest in aSyn species as potential biomarkers for early diagnosis of PD and differentiate it from other synucleinopathies. In this review, we (1) provide an overview of the progress toward mapping the distribution of aSyn species in the brain, peripheral tissues, and biological fluids; (2) present comparative and critical analysis of previous studies that measured total aSyn as well as other species such as modified and aggregated forms of aSyn in different biological fluids; and (3) highlight conceptual and technical gaps and challenges that could hinder the development and validation of reliable aSyn biomarkers; and (4) outline a series of recommendations to address these challenges. Finally, we propose a combined biomarker approach based on integrating biochemical, aggregation and structure features of aSyn, in addition to other biomarkers of neurodegeneration. We believe that capturing the diversity of aSyn species is essential to develop robust assays and diagnostics for early detection, patient stratification, monitoring of disease progression, and differentiation between synucleinopathies. This could transform clinical trial design and implementation, accelerate the development of new therapies, and improve clinical decisions and treatment strategies.

NATURE PORTFOLIO2022

Exploring the pathological interaction between LRRK2 and alpha-synuclein

Alessandra Musso

Parkinson’s disease (PD) is the most common age-related neurodegenerative movement disorder that affects 1-2% of the general population over the age of 65 and rising to 4-5% over 80 years of age. It is estimated that 6.3 million people worldwide have Parkinson’s disease and 1.2 million in the European Union (EU) alone. As the disease progresses, patients frequently develop a mask-like facial expression, festinating gait and cognitive impairment and the final clinical symptoms are muscle rigidity, bradykinesia, resting tremor and postural instability in addition to non-motor problems that result in a marked reduction in quality of life. The motor symptoms of PD arise from the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) leading to a deficiency of the neurotransmitter dopamine (DA) in the striatum. While dopamine replacement therapy is initially effective in treating the motor symptoms of PD, there is no known cure or neuroprotective therapy for this debilitating disease. Although the pathology underlying the disease is well defined, it is still unclear why DAergic neurons degenerate and die. PD is generally considered as a sporadic disease of unknown etiology, however in the last two decades it has become clear that heritability plays an important role in the pathogenesis of PD. Of the different genes associated with familial disease, mutations in two genes encoding for α-synuclein and leucine-rich repeat kinase 2 (LRRK2) proteins cause autosomal dominant PD. One of the neuropathological hallmarks of idiopathic and some familial forms of PD are Lewy bodies, which are intracytoplasmic inclusions that are enriched with fibrillar α- synuclein protein. Notably, LRRK2 mutation carriers with PD predominantly develop Lewy body pathology suggesting that LRRK2 may lie upstream of α-synuclein aggregation. These observations and other in vivo studies have suggested a common pathogenic pathway with LRRK2 potentially regulating the aggregation and neuronal toxicity of α-synuclein. However, the relationship between LRRK2 and α-synuclein in the mammalian brain is presently unclear and requires further evaluation, especially within midbrain dopaminergic neurons that degenerate in PD. The aim of this thesis work was to delineate a potential pathogenic interplay between these two PD-related gene products in mediating neurodegeneration in vivo. Understanding how and where the functional pathways of LRRK2 and α-synuclein converge will provide important insight into the common mechanisms underlying neurodegeneration in PD.[...]

EPFL2014

Microfluidics and cell-free synthetic biology in the development of new diagnostic and therapeutic platforms

Grégoire Michielin

In phenylketonuria, absence or malfunction of the phenylalanine hydroxylase enzyme results in toxic accumulation of phenylalanine in the body. An injectable recombinant enzyme therapy was recently approved and has the potential to improve the quality of life of patients with phenylketonuria.Cell-free protein production uses cytosolic extract of prokaryotic or eukaryotic cells and has the potential to offer flexibility in biomanufacturing at different scales, accelerating prototyping, and allowing decentralized production of therapies by using freeze-dried protein expression systems.In this thesis, we show that we can express the therapeutic enzyme phenylalanine ammonia lyase in home-made cell-free protein expression systems. By using a spectrophotometric enzymatic assay, we show that the enzyme is active and converts phenylalanine to the non-toxic metabolite trans-cinnamic acid. The cell-free expression system can be freeze-dried and still produces active therapeutic enzyme, which would allow the decentralized production of this enzyme replacement therapy. However, the cost associated per dose would be too high with the current cell-free expression system. Improvements will be required in protein yields and costs per reaction to offer decentralized production of enzyme replacement therapy for phenylketonuria.Another opportunity to improve the quality of life of patients with phenylketonuria would be to propose an oral enzyme replacement therapy. For this purpose, we developed a platform to produce biocompatible semi-permeable microcapsules made of poly-(PEG-DA 250 g/mol) to encapsulate the therapeutic enzyme and protect it from proteolytic digestion. Our results show that the microcapsules are semi-permeable, thermally and mechanically stable, and resistant to incubation in simulated gastric and intestinal fluid. Proteins and active enzymes were successfully encapsulated, but the pore size was slightly too large and would allow the transport of proteolytic enzymes across the capsules shell, thus requiring further improvements for the oral enzyme replacement therapy of phenylketonuria. To demonstrate the potential of the semi-permeable capsules for different applications, we encapsulated proteins, enzymes, magnetic beads, DNA, bacteria or yeast cells inside the liquid core of the microcapsules. Forward-looking, this biocompatible microencapsulation platform could be used in the building of innovative encapsulated diagnostic and therapeutic systems containing active biomolecules or living cells.During the COVID-19 pandemic, we developed a solution to help in the conduction of serological epidemiological studies for the detection of anti-SARS-CoV-2 antibodies. We integrated a decentralized capillary blood collection, dried blood samples shipping, and centralized processing and analysis on a microfluidic chip for high-throughput nano-immunoassays. The microfluidic assay analyzes sample with volumes of a few nanoliters and reduces reagents consumption per datapoint by 2 or 3 orders of magnitude thus offering the potential to greatly reduce costs. The nano-immunoassay was validated with serum samples from 155 PCR-confirmed patients and 134 pre-pandemic negative control sera and showed 100% specificity and 98% sensitivity in duplicate measurement. We also show evidence of the good performance of collecting dried blood spots with glucose test strips or two commercial microsampling devices followed by testing with the nano-immunoassay.

EPFL2021