Etude des altérations des cycles éveil/sommeil dans des modèles de la maladie de Parkinson et de l’atrophie multisystématisée
(Study of sleep/wake alterations in mouse models of Parkinson’s disease et Multiple System Atrophy)
Defense in french
Thesis supervisor : Erwan Bézard
Abstract
Parkinson’s disease (PD) and Multiple System Atrophy are both synucleinopathies. These diseases are characterized by the loss of dopaminergic neurons of the substantia nigra pars compacta (SNc) and the presence of cytoplasmic inclusions. These inclusions are named Lewy Bodies (LB) in PD and glial cytoplasmic inclusions (GCI) in MSA and contain notably misfolded alpha-synuclein (a‑syn). In addition to movement disorders, PD and MSA patients exhibit a myriad of non-motor symptoms including sleep/wake alterations that may occur early in the course of the diseases and that are even considered as predictors of synucleinopathies. The aim of my thesis is thus to investigate the likelihood of a relationship between the progression of neurodegeneration, the progression of the a‑syn pathology, and the occurrence of sleep/wake issues.
First, as the loss of DA neurons is a characteristic of synucleinopathies, we studied the impact of dopamine depletion on sleep. This study tends to show that dopamine has a role in the maintenance of arousal phases.
We then used a mouse model of PD which consists of the intracerebral injection of LB fractions containing pathological a-syn to study possible alterations of the wake/sleep cycles. A few months after the injection of these fractions, several sleep parameters appear altered, including the total time spent awake or asleep. This model, therefore, appears adequate for the subsequent study of the impact of alterations in the wake/sleep cycle on the development of the pathology. In contrast, no alteration was observed in the AMS model studied, namely the PLP-syn mice. More studies are therefore needed on other models of the disease.
Finally, since sleep has a known role in protein elimination, we have studied its impact on the pathology associated with a-syn.
The work carried out is particularly relevant because understanding whether alterations in the wake/sleep cycles can be used at the experimental level as a marker of the progression of the pathology could allow early detection and lead to new therapeutic strategies to slow down its progression. This work is of particular relevance as understanding if sleep disorders may serve experimentally as a surrogate marker of neurodegeneration or pathology progression could provide an early way detection and lead to new therapeutic strategies to slow down its progression.
Keywords: sleep; animal modeling; synuclein; human pathology
Publications
Yu X.°, Persillet M.°, Zhang L., Zhang Y., Xiuping S., Li X., Ran G., S. Breger L.S., Dovero S., Porras G., Dehay D., Bezard E., Qin C. (2021), Evaluation of blood flow as a route for propagation in experimental Synucleinopathy, Neurobiology of disease
Decoeur F., Benmamar-Badel A., Leyrolle Q., Persillet M., Layé S., Nadjar A. (2020) Dietary N-3 PUFA deficiency affects sleep-wake activity in basal condition and in response to an inflammatory challenge in mice, Brain, Behavior, and Immunity
Jury
– Pierre-Hervé LUPPI – Directeur de recherche, CNRS
– Véronique FABRE – Chargée de recherche, INSERM
– Ana MARQUES – Praticien hospitalier, CHU de Clermont-Ferrand
– Agnès NADJAR – Professeure des Universités, Université de Bordeaux
– Erwan BEZARD – Directeur de recherche, INSERM
Marine Persillet
Team Pathophysiology of parkinsonian syndromes
IMN