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Multifactorial and translational approaches for modeling synucleinopathies : mechanistic and therapeutic implications

Abstract : My thesis project was dedicated to the study of synucleinopathies. Synucleinopathies are neurodegenerative diseases characterized by the presence of alpha-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 alpha-synuclein-mediated mechanisms of neurodegeneration using a non-human primate model of Parkinson’s disease. We confirmed the toxic role of alpha-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 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 alpha-synuclein between the CNS and the ENS and within the ENS. Finally, we focused on the restoration of the autophagic function as a potential common therapeutic target for all synucleinopathies. We demonstrated through a gene-based restoration of the autophagy, we efficiently reestablish alpha-synuclein physiological protein levels, while inducing neuroprotection in a Parkinson’s disease and Multiple system atrophy rodent models. Thus, this work corroborates the key role of alpha-synuclein in the etiology of synucleinopathy and offers new common therapeutic strategies for all synucleinopathies to decrease alpha-synuclein-induced toxicity into the central nervous system.
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Submitted on : Thursday, November 14, 2019 - 10:49:23 AM
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Marie-Laure Arotcarena. Multifactorial and translational approaches for modeling synucleinopathies : mechanistic and therapeutic implications. Neurons and Cognition [q-bio.NC]. Université de Bordeaux, 2019. English. ⟨NNT : 2019BORD0164⟩. ⟨tel-02363002⟩

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