PhD: Mathieu Bourdenx

Modelling multi-factorial neurodegeneration in Parkinson’s disease

Defended on December 11, 2015

PhD student with grant from LabEx BRAIN.

The aim of this work was to focus on neurodegenerative mechanisms in the context of synucleinopathies, especially on Parkinson’s disease (PD). PD is characterized by the loss of dopaminergic neurons and the presence of intracytoplasmic proteinaceous inclusions named Lewy Bodies of which α-synuclein (α-syn) is the main protein component. To date, there are no curative treatments. Elucidating mechanisms underlying neurodegeneration in PD will allow the identification of new molecular targets for therapeutic intervention. My Ph.D. work intends multifactorial and translational approaches based on modelling, therapeutic intervention and mechanistic studies. We first focused on the development of new animal models of PD based on the use of viral vectormediated overexpression of α-syn. This word allowed us to conclude on the absence of additive effect of ageing in α-syn-related toxicity, at least in the three investigated species. Then, we worked on two therapeutic strategies to overcome the lysosomal dysfunction occurring in PD. To do so, we first developed a biotechnological approach based on the use of acidic nanoparticles restoring acidic pH of sick lysosomes, and then we used a gene therapy approach based on the overexpression on a central modulator lysosomal biogenesis. We here demonstrated the interest of restoration of lysosomal physiology. Finally, we tested the “prion-like” hypothesis in a cohort of non-human primates and assessed the efficacy of a therapeutic approach using an oligomer modulator in mice. This work highlights the central role of α-syn in PD aetiology and offers innovative strategies for both modelling and therapeutic intervention. 

Keywords : α-synuclein, Parkinson’s disease, adeno-associated viruses, animal models, rodent, non-human primate, protein aggregation, nanoparticles, autophagy, lysosomes.

 

Publications

Bourdenx M, Daniel J, Genin E, Blanchard-Desce M, Bezard E, Dehay B (2015) Nanoparticles restore lysosomal acidification defects: Implication for Parkinson’s and other lysosomal-related diseases. Autophagy (In press)

Bourdenx M, Dovero S, De Deurwaerdère P, Li Q, Bezard E (2015) Early prenatal exposure to MPTP does not affect nigrostriatal neurons in Macaque Monkey. Synapse (In press)

Bourdenx M et al. (2015a) Lack of additive role of ageing in nigrostriatal neurodegeneration triggered by alpha-synuclein overexpression. Acta neuropathologica communications 2015 Jul 25;3(1):46.

Bourdenx M, Dehay B, Gorry P, Przedborski S, Vila M, Hunot S, Singleton A, Olanow CW, Merchant KM, Bezard E, Petsko GA, Meissner WG. (2015b). Targeting α-synuclein for treatment of Parkinson’s disease: mechanistic and therapeutic considerations. Lancet Neurol. Aug;14(8):855-66.

Bourdenx M, Koulakiotis NS, Sanoudou D, Bezard E, Dehay B, Tsarbopoulos A (2015c) Protein aggregation and neurodegeneration in prototypical neurodegenerative diseases: Examples of amyloidopathies, tauopathies and synucleinopathies. Progress in neurobiology. 2015 Jul 21. pii: S0301-0082(15)00077-5.

Barroso-Chinea P, Thiolat ML, Bido S, Martinez A, Doudnikoff E, Baufreton J, Bourdenx M, Bloch B, Bezard E, Martin-Negrier ML (2015d) D1 dopamine receptor stimulation impairs striatal proteasome activity in Parkinsonism through 26S proteasome disassembly. Neurobiology of disease.

Bastide, M.F., Meissner, W.G., Picconi, B., Fasano, S., Fernagut, P.O., Feyder, M., Francardo, V., Alcacer, C., Ding, Y., Brambilla, R., Fisone, G., Jon Stoessl, A., Bourdenx, M., Engeln, M., Navailles, S., De Deurwaerdere, P., Ko, W.K., Simola, N., Morelli, M., Groc, L., Rodriguez, M.C., Gurevich, E.V., Quik, M., Morari, M., Mellone, M., Gardoni, F., Tronci, E., Guehl, D., Tison, F., Crossman, A.R., Kang, U.J., Steece-Collier, K., Fox, S., Carta, M., Angela Cenci, M., Bezard, E., (2015e). Pathophysiology of L-dopa-induced motor and non-motor complications in Parkinson’s disease. Progress in neurobiology 132, 96-168.

Engeln M, Bastide MF, Toulme E, Dehay B, Bourdenx M, Doudnikoff E, Li Q, Gross CE, Boue-Grabot E, Pisani A, Bezard E, Fernagut PO (2014a) Selective Inactivation of Striatal FosB/DeltaFosB-Expressing Neurons Alleviates L-Dopa-Induced Dyskinesia. Biological psychiatry.

Bourdenx M, Bezard E, Dehay B (2014b) Lysosomes and alpha-synuclein form a dangerous duet leading to neuronal cell death. Frontiers in neuroanatomy 8:83.

Bourdenx M, Dehay B, Bezard E (2014c) Down-regulating alpha-synuclein for treating synucleopathies. Movement disorders : official journal of the Movement Disorder Society 29:1463-1465
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Bourdenx M, Dutheil N, Bezard E, Dehay B (2014d) Systemic gene delivery to the central nervous system using Adeno-associated virus. Frontiers in molecular neuroscience 7:50.

Bourdenx M, Nilsson A, Wadensten H, Falth M, Li Q, Crossman AR, Andren PE, Bezard E (2014e) Abnormal structure-specific peptide transmission and processing in a primate model of Parkinson’s disease and l-DOPA-induced dyskinesia. Neurobiology of disease 62:307-312.

Jury

  • Dr. BROUILLET Emmanuel Directeur de recherche CEA Président
  • Dr. GASNIER Bruno Directeur de recherche Université Paris Descartes Rapporteur
  • Dr. BUEE Luc Directeur de recherche Université Lille 2 Rapporteur
  • Dr. DEHAY Benjamin Chargé de recherche Université de Bordeaux Invité
  • Dr. BEZARD Erwan Directeur de recherche Université de Bordeaux Directeur de thèse

PhD supervisor

Erwan Bézard
Directeur de recherche INSERM
Directeur de l’Institut des Maladies Neurodégénératives
Responsable de l’équipe – Physiopathologie des syndromes parkinsoniens. 

Publications

Last update: 6 April 2018