Venue: Centre Broca / Auditorium
Defense in english
Mechanistic study and potential therapeutic targets of synucleinopathies
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.
– François Tison
– Laura Parkkinen
– Tiago Outeiro
– Benjamin Dehay
- A New Rise of Non-Human Primate Models of Synucleinopathies
Margaux Teil, Marie-Laure Arotcarena, Benjamin Dehay.
Biomedicines. 2021-03-09. 9(3) : 272.
- L‐DOPA regulates α‐synuclein accumulation in experimental parkinsonism
Marc Deffains, Marie‐Hélène Canron, Margaux Teil, Qin Li, Benjamin Dehay, Erwan Bezard, Pierre‐Olivier Fernagut.
Neuropathol Appl Neurobiol. 2020-12-04.
- Targeting α-synuclein for PD Therapeutics: A Pursuit on All Fronts
Margaux Teil, Marie-Laure Arotcarena, Emilie Faggiani, Florent Laferriere, Erwan Bezard, Benjamin Dehay.
Biomolecules. 2020-03-03. 10(3) : 391.
- Autophagy in Synucleinopathy: The Overwhelmed and Defective Machinery
Marie-Laure Arotcarena, Margaux Teil, Benjamin Dehay.
Cells. 2019-06-09. 8(6) : 565.
/ Team: Physiopathologie des syndromes parkinsoniens (IMN)
Supervisor: Benjamin Dehay