Marie-Laure Arotcarena

Approches multifactorielles et translationnelles dans la modélisation des synucleinopathies : Implications mécanistiques et thérapeutiques

septembre 2019 Directeur(s) de thèse : Benjamin Dehay Résumé de thèse

Synucleinopathies are neurodegenerative diseases characterized by the presence of α-synuclein-positive intracytoplasmic inclusions which are present either in neurons for Parkinson’s disease (i.e. Lewy Bodies) or in oligodendrocytes for Multiple system atrophy (i.e. Glial Cytoplasmic Inclusions).

The aim of my work was to establish a multifactorial and translational approach through modeling, mechanistic and therapeutic aspects associated with synucleinopathies. First, we focused on dissecting the underlying α-synuclein-mediated mechanisms of neurodegeneration using a non-human primate model of Parkinson’s disease. We confirmed the toxic role of α-synuclein in the pathology and highlighted unpredictable cellular processes involved in neurodegeneration. Using the same Parkinson’s disease model, we studied the hypothesis of a pathological propagation of α-synuclein between the central and peripheric nervous systems in an attempt to decipher the initiation point and the direction of propagation of the associated pathology. We thus demonstrated a bidirectional route of propagation of α-synuclein between the central and enteric nervous systems.

Finally, we focused on the restoration of the autophagic function as a potential common therapeutic target for all synucleinopathies. Through a gene-based restoration of autophagy, we efficiently reestablished α-synuclein physiological protein levels, while inducing neuroprotection in Parkinson’s disease and Multiple system atrophy rodent models. Thus, this work corroborates the key role of α-synuclein in the etiology of synucleinopathy and offers new common therapeutic strategies for all synucleinopathies to decrease α-synuclein-induced toxicity in the central nervous system.

Keywords: neuropathology, neurodegeneration, synucleinopathy, mechanistic, therapeutic.