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Thesis defense – Margaux Teil

Name: <span>Thesis defense – </span>Margaux Teil
Start: 2021-11-25T14:00:00+01:00
End: 2021-11-25T14:00:00+01:00

25 November 2021 / 14:00

Venue: Centre Broca / Auditorium

Defense in english

Title

Mechanistic study and potential therapeutic targets of synucleinopathies

Abstract

My thesis focused on the study of synucleinopathies, a family of neurodegenerative diseases. The three main synucleinopathies are Parkinson’s disease, multiple system atrophy, and dementia with Lewy bodies. These diseases are characterized by the loss of neurons in various brain regions and the presence of intracytoplasmic α-synuclein-positive inclusions. These inclusions are located either in neurons (Lewy bodies) or in oligodendrocytes (Glial cytoplasmic inclusions). The trigger and cause for the formation of these inclusions remain unknown, and no curative treatments currently exist. The objective of my thesis was to study the neurodegenerative mechanisms and potential therapeutic strategies of these synucleinopathies. For this, I was first interested in the mechanisms implicated in the transmission of α-synuclein from multiple system atrophy patients. This allowed us to develop a potential new model to study multiple system atrophy in both mice and non-human primates by spreading of α-synuclein within the brain. In the second part, we wanted to investigate potential therapeutic targets in the same model of Parkinson’s disease. This study confirmed the efficacy and pertinence of three different strategies that target various mechanisms of Parkinson’s disease to induce the protection of dopaminergic neurons of the substantia nigra in a mouse model. By modulating zinc levels, we demonstrated the importance of zinc concentrations in the brain and the therapeutic interest in targeting metal homeostasis via specific chelators. We then used viral vectors to overexpress a transcription factor implicated in dopaminergic neuron survival, oxidative stress and proteasome activity in the substantia nigra of a mouse model of Parkinson’s disease. Finally, we used a small anti-aggregative molecule to determine its efficacy in protecting neurons in the same mouse model. Altogether, this thesis work showed the implication of α-synuclein in triggering and propagating synucleinopathies, the importance of targeting this protein, and other dysregulated cellular mechanisms to discover potential therapies.