Venue : Centre Broca
Rémi Kinet
Team : Pathophysiology of proteinopathies
IMN
Thesis directed by Benjamin Dehay
Title
Study of Nanovectors for lysosome-based therapeutic strategies against neurodegenerative diseases
Abstract
My PhD project was multifactorial and interdisciplinary, focusing on the characterization, modeling, and treatment of neurodegenerative diseases linked to the autophagic mechanism. Neurodegenerative diseases share the common feature of progressive death of specific neuronal populations in different regions of the nervous system. Most neurodegenerative diseases are classified within the family of proteinopathies, as they are characterized by the aggregation of pathological proteins that play a major role in the pathogenic process. Although the pathogenic mechanisms underlying these diseases are not yet fully understood, numerous studies have shown that the autophagic pathway and its final organelle, the lysosome, are impaired and thus contribute to the pathogenic process by failing to degrade the protein aggregates that mark these diseases. This cellular clearance pathway has therefore emerged as a promising therapeutic target in the search for treatments for proteinopathies. To enable the development of a treatment applicable to animal models, my work focused on three main axes: (i) in vivo modelling of Parkinson’s disease through the ATP13A2 gene, which is linked to the autophagic mechanism; (ii) characterization of non-human primate models of neurodegenerative diseases to better understand and evaluate the different pathophysiological alterations in proteinopathies; and (iii) targeting the lysosome for therapeutic purposes in Parkinson’s disease.
Our studies led to the characterization of new animal species with ATP13A2 protein deficiency, in both rats and non-human primates, displaying a parkinsonian phenotype and a significant impairment of the autophagic pathway. Furthermore, these models support the activation of compensatory neuroprotective mechanisms in ATP13A2 knockout animals induced at the embryonic stage. In addition, modelling of Parkinson’s and Alzheimer’s diseases through intracerebral injection of pathological protein extracts from patients into non-human primates validated the prion-like hypothesis proposed for these diseases. Moreover, the characterization of different pathophysiological dynamics was revealed depending on the type of aggregates inoculated. Finally, to restore autophagic function, particularly lysosomal activity, the team previously attempted to reacidify the lysosomal lumen using poly(lactic-co-glycolic acid) nanoparticles or trehalose, a natural disaccharide known to enhance the biogenesis of autophagic vacuoles. In this project, the goal was to produce and test a polymersome-based nanocarrier capable of crossing the blood–brain barrier and specifically targeting dopaminergic neurons through the conjugation of glucose and DCP (a dopamine agonist) groups on its corona, enabling the co-delivery of two active molecules. The results showed that the polymersomes were able to enter dopaminergic neurons of the substantia nigra following intracerebral, intranasal, and retro-orbital injections, and to reach the lysosomes. Moreover, we demonstrated both in vitro and in vivo that polymersome treatment led to a physiological reacidification of the lysosomal lumen. Finally, an increase in autophagic flux induced by the release of trehalose encapsulated within the polymersome was observed. These findings position this acidic polymersome-based therapy encapsulating trehalose as a promising treatment for Parkinson’s disease, as well as for other neurodegenerative diseases, owing to the versatility and tunability of its components.
Key words
Polymersome, lysosome, therapy, animal model
Publications
- Kinet R*, Bourdenx M*, et al. Differential pathological dynamics triggered by distinct Parkinson patient-derived α-synuclein extracts in nonhuman primates. Science Advances. 2025;11-25 doi: 10.1126/sciadv.adu6050
- Darricau M*, Dou C*, Kinet R, et al. Tau seeds from Alzheimer’s disease brains trigger tau spread in macaques while oligomeric-Aβ mediates pathology maturation. Alzheimers Dement. 2024;20(3):1894-1912. doi:10.1002/alz.13604
- Brouillard M, Kinet R, Joyeux M, Dehay B, Crauste-Manciet S, Desvergnes V. Modulating Lysosomal pH through Innovative Multimerized Succinic Acid-Based Nucleolipid Derivatives. Bioconjug Chem. 2023;34(3):572-580. doi:10.1021/acs.bioconjchem.3c00041
- Kinet R, Dehay B. Pathogenic Aspects and Therapeutic Avenues of Autophagy in Parkinson’s Disease. Cells. 2023;12(4):621. Published 2023 Feb 15. doi:10.3390/cells12040621
- Marie A, Kinet R, Helbling JC, et al. Impact of dietary vitamin A on striatal function in adult rats. FASEB J. 2023;37(8):e23037. doi:10.1096/fj.202300133R
- Sikora J*, Dovero S*, Kinet R, et al. Nigral ATP13A2 depletion induces Parkinson’s disease-related neurodegeneration in a pilot study in non-human primates. NPJ Parkinsons Dis. 2024;10(1):141. Published 2024 Aug 1. doi:10.1038/s41531-024-00757-4
* co-premier auteur
Jury
Dr. MURA Simona, Université Paris-Saclay, Rapporteuse
Dr. MOLLEREAU Bertrand, École Normale Supérieure de Lyon, Rapporteur
Dr. BOMONT Pascale, Université de Lyon, Examinatrice
Dr. FRISCOURT Frédéric, Institut Européen de Chimie et Biologie, Examinateur
Dr. DEHAY Benjamin, Université de Bordeaux, Directeur de thèse