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Thesis defense – Marie-Laure Arotcarena

Monday 30 September 2019 / 14:00

Approches multifactorielles et translationnelles dans la modélisation des synucléinopathies : implications mécanistiques et thérapeutiques

Venue: Centre Broca Nouvelle-Aquitaine / Salle de conférence


Marie-Laure Arotcarena
IMN – Pathophysiology of parkinsonian syndromes

Thesis supervisor : Benjamin Dehay

Summary

My thesis project was dedicated to the study of synucleinopathies. Synucleinopathies are neurodegenerative diseases characterized by the presence of a-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 a-synuclein-mediated mechanisms of neurodegeneration using a non-human primate model of Parkinson’s disease. We confirmed the toxic role of a-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 α-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 a-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 a-synuclein in the etiology of synucleinopathy and offers new common therapeutic strategies for all synucleinopathies to decrease a-synuclein-induced toxicity into the central nervous system.

Publications

En révision :

Arotcarena, M.L; Dovero, S; Prigent, A; Bourdenx, M; and al., Bidirectional gut-to-brain and brain-to-gut propagation of α-synuclein pathology in non-human primates. 1st co-author.

Bourdenx, M; Nioche, A; Dovero, S; Arotcarena M.L and al., Machine learning reveals different pathological signatures of patient-derived α-synuclein extracts in non-human primates. 1st co-author.

Publié :

Arotcarena, M.-L. Bourdenx, M. et al. Transcription factor EB overexpression prevents neurodegeneration in experimental synucleinopathies. JCI Insight. 2019;4(16):e129719. https://doi.org/10.1172/jci.insight.129719

Arotcarena, M.L and B. Dehay, Les synucléinopathies sont-elles des maladies à prions ? Pratique Neurologique FMC (2018), 2018. https://doi.org/10.1016/j.praneu.2018.02.006

Arotcarena ML, Teil M, Dehay B (2019) Autophagy in Synucleinopathy: The Overwhelmed and Defective Machinery. Cells (2019), 8(6), 565; https://doi.org/10.3390/cells8060565

Jury

Nadine Camougrand (DR2, CNRS) – IBGC – Bordeaux (Présidente du jury)

Olga Corti (DR2, INSERM) – Institut du cerveau et de la Moelle épinière (ICM), Paris (Rapporteur)

Philippe Hantraye (DR1, CNRS) – Institut de Biologie François Jacob, MIRCen, CEA, Paris-Saclay (Rapporteur)

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Details

Date:
Monday 30 September 2019
Time:
14:00
Event Category: