Maladie à corps de Lewy

Résumé

La maladie à corps de Lewy (MCL), appelée aussi démence à corps de Lewy (DCL), est un type de démence partageant des caractéristiques avec la maladie d'Alzheimer et la maladie de Parkinson. Plus précisément, ce sont la maladie d'Alzheimer et la maladie de Parkinson qui partagent des caractéristiques avec la MCL, rendant difficile la distinction diagnostique entre ces deux dernières maladies. Un patient atteint de la maladie de Parkinson ou d'un syndrome parkinsonien peut aussi développer une MCL en parallèle (risque quatre fois plus important dans ce cas). La MCL se manifeste par des troubles cognitifs d'évolution progressive et fluctuante, associés à des hallucinations visuelles et à un syndrome extrapyramidal. De toutes les démences répertoriées dans le corps médical, y compris celles incluant les hallucinations rencontrées dans les délires paranoïaques ou schizophrènes, la MCL est la plus lourde et la plus sévère. Elle réunit aussi souvent les caractéristiques et manifestations

Source officielle

https://fr.wikipedia.org/wiki/Maladie_%C3%A0_corps_de_Lewy

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The course starts with fundamentals of electrical - and chemical signaling in neurons. Students then learn how neurons in the brain receive and process sensory information, and how other neurons control the behavior of an animal. Furthermore, memory, learning, and brain disorders will be introduced.

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DJ-1 as a neuroprotective protein in models of Parkinson's disease

Katarzyna Piorkowska-Stanco

Parkinson's disease (PD) is a common progressive neurodegenerative disorder characterized clinically by the combination of motor symptoms like bradykinesia, tremor, rigidity and postural instability. The pathology of PD is related to the degeneration of dopaminergic neurons of the substantia nigra pars compacta (SNpc) leading to the deficiency of dopamine in the striatal projection areas of these neurons. The pathogenesis of PD is not fully elucidated yet, however there is strong evidence that protein aggregation, mitochondrial dysfunction and oxidative stress play a primary role in the etiology of the disease. Most of PD cases are sporadic, however, several genes have been characterized to cause familial forms of the disease. Among them, mutations in DJ-1 were identified in families with autosomal-recessive early-onset PD and account for 2% of inherited PD cases. The DJ-1 protein was identified as an important player in cellular defense against oxidative stress as it possibly acts as an oxidative stress-induced chaperone and inhibits the formation of inclusions of α-synuclein, another protein related to PD. Alpha-synuclein mutations cause an autosomal dominant form of the disease. Moreover, this protein is a main component of Lewy Bodies, a pathological hallmark of PD. The goal of the experiments during my thesis was to investigate the potential protective effect of DJ-1 in toxin-based [6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)] as well as genetic models of PD in vivo. Towards this goal, the DJ-1 protein was over-expressed in rodent SNpc through the injections of recombinant adeno-associated viral vector (rAAV). In the first study, the DJ-1 over-expression led to significant protection of dopaminergic cells and spontaneous motor behavior in 6-OHDA-lesioned animals. However, this effect of DJ-1 was not confirmed when DJ-1 was over-expressed in the brains of mice lesioned with MPTP. In the third part of the study, the nigral over-expression of mutated a-synuclein (A30P mutation found in familial PD cases) was chosen as the genetic model of PD, already developed in our lab. Interestingly, significant preservation of spontaneous behavior was obtained when a-synuclein (A30P) was co-injected with DJ-1. However, this was accompanied by a modest protection of dopaminergic cells, suggesting the implication of other, subtle mechanisms regulating DJ-1-related basal ganglia output. Although the DJ-1 protection of dopaminergic cells was not always achieved, the effect of DJ-1 on the spontaneous behavior implies the interesting capacity of this protein. Our results suggest that DJ-1 is one of key factors playing role in maintenance of dopaminergic function. For a possible clinical application, DJ-1 may have to be linked with another neuroprotecting factor to assure a stronger protection effect.

EPFL2007

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Although it has been nearly two and half decades since the discovery of alpha-synuclein (aSyn) as the major component of Lewy bodies (LBs), our understanding of the involvement of different aSyn species, their seeding, spreading and toxicity in Parkinson's disease (PD) is limited. One of the major causes underlying this knowledge gap is the unavailability of adequate tools, techniques, and model systems to capture, monitor, and evaluate the role of different aSyn species in the disease process. In addition, our understanding of cell-type specific contributions to disease pathogenesis is limited. In this thesis, we systematically address the current knowledge gaps and elucidate the structural and cellular determinants of aSyn seeding and toxicity using cellular and animal model systems of PD. In the first chapter of this thesis, we describe an antibody characterization and validation pipeline to assess the specificity of antibodies to well-characterized preparations of various aSyn species, including monomers, fibrils, and different type of oligomers. Using an array of techniques, we demonstrate that that: i) none of the antibodies tested are specific for one particular type of aSyn species, including monomers, oligomers or fibrils; ii) all antibodies that were reported to be oligomer-specific also recognized fibrillar aSyn; and iii) a few antibodies (e.g., the antibody clone 26F1, 5G4) showed high specificity for oligomers and fibrils but did not bind to monomers. These findings suggest that most aSyn aggregate-specific antibodies cannot be used to differentiate between oligomers and fibrils, thus highlighting the importance of exercising caution when interpreting results obtained using these antibodies. In the second chapter of this thesis, we systematically addressed the current knowledge gaps on the role of aSyn oligomers in the initiation, seeding and pathology spreading. Towards this goal, we used different biophysical approaches to investigate aSyn seeding in vitro and in neurons and animal models of aSyn seeding and pathology spreading. we observed that oligomeric forms do not form in the PFF-based neuronal seeding model and we report that different types of oligomers do not seed pathology in vitro and primary hippocampal neurons, and their presence slows rather than accelerates aSyn fibrillization. Altogether, our work points to fibrils as the most seeding competent species and suggests that they are the critical mediators of pathology spreading in PD and other synucleinopathies.In the third chapter of this thesis, we used single-nuclei RNA-sequencing to investigate transcriptional changes in different cell types of the amygdala brain region, which is highly susceptible to developing pS129 positive aggregates in the PD brains. We identified that most of the top 100 differentially expressed genes (DEGs) are of neuronal rather than non-neuronal cell types. In addition, we report that the gene expression profile of a handful of PD risk genes such as Sncaip, Park7, Maob, Hspa8, Scl2a3 and Hsf3 and some pathways that have been associated with PD are differentially altered in specific cell types. Our study highlights the involvement of unique gene expression changes and their associated pathways in different cell types in driving the disease process at an early stage in a PFF-based mouse model of PD.

EPFL2022

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Synucleinopathies such as Parkinson's disease, dementia with Lewy bodies and multiple system atrophy (MSA) are detrimental neurodegenerative diseases. Alpha-synuclein (aSyn), the main aggregating protein found in the pathological inclusions of these ailments, exists in numerous modified forms and conformations, leading to neuropathological heterogeneity in synucleinopathies. The functional, pathological and clinical implications of this heterogeneity remain unclear. Responding this knowledge gap requires the development of novel toolsets capable of capturing the biochemical and structural diversity of aSyn pathology in the brain and peripheral tissues.To address this challenge, we describe in Chapter 2 the development and characterisation of antibodies that cover all three regions and post-translational modifications (PTMs) of aSyn. We assess these antibodies through a comprehensive validation pipeline, and select the best performing antibody subset to capture the neuropathological diversity of aSyn across Lewy body diseases (LBDs). We demonstrate that these antibodies could be used to achieve an in-depth characterization of the biochemical and morphological diversity of aSyn aggregates in the neuronal and in vivo models of aSyn seeding. Our results suggest that aSyn pathology is rich in Serine 129 phosphorylation (pS129) and in previously under-described PTMs, including nitration and phosphorylation at Tyrosine 39 (nY39, pY39) and C-terminal tyrosine phosphorylations (pY133, pY136) across neuronal and glial populations in LBDs. We also report that aSyn is hyperphosphorylated in the cellular and in vivo seeding models. In Chapter 3, we demonstrate the power of our antibodies to achieve an unprecedented analysis of astrocytic aSyn pathology in LBDs. We characterise the biochemical properties, post-translational modifications and the aggregation state of astrocytic aSyn accumulations in the limbic regions across sporadic and familial LBDs. The astrocytic aSyn is revealed distinctively by antibodies against the late amino-terminus (N-terminus) and non-amyloid-beta component (NAC) region of aSyn, but not by the extreme N-terminal or carboxy-terminal (C-terminal) antibodies, suggesting that these aSyn species are truncated at both ends. The astrocytic aSyn accumulations are negative for the key markers of Lewy bodies (aSyn pS129, Amytracker, p62- and ubiquitin-positivity and proteinase K resistance), and positive for aSyn nY39 and pY39. These findings suggest that the astrocytic accumulations may be composed of non-fibrillar, possibly oligomeric conformers of aSyn. Chapter 4 focuses on deciphering the biochemical and morphological signatures of aSyn pathology in MSA. The antibodies described in Chapter 2 are applied to high and low pathology regions of MSA brains by immunohistochemistry (IHC). We also biochemically profile the aSyn species, and report an abundance of aSyn pS129-positive glial and neuronal inclusions that correspond to insoluble high molecular weight species by Western blot. We detect an enrichment of insoluble and truncated aSyn in the MSA cerebellum. By IHC, there is an enhancement of aSyn nY39, pY136 and of other aSyn PTMs.Collectively, the new tools and findings described here may pave the way for future studies elucidating the role of these neuronal and glial aSyn proteoforms in disease pathogenesis and propagation in synucleinopathies.

EPFL2022

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EPFL2022

DJ-1 as a neuroprotective protein in models of Parkinson's disease

Katarzyna Piorkowska-Stanco

EPFL2007