Pathophysiology of parkinsonian syndromes, Bordeaux – Jan 2017 CFATG
Pathophysiology of parkinsonian syndromes, Bordeaux – Jan 2017
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Pathophysiology of parkinsonian syndromes

Address : Institut des Maladies Neurodégénératives
Université de Bordeaux
CNRS UMR 5293 – Bât. Neurocampus
146 Rue Léo Saignat
33076 Bordeaux – France
Tél. : +33 557 571 540
Fax : +33 556 986 182

Presentation of the team

Web site : http://www.imn-bordeaux.org/en/teams/pathophysiology-of-parkinsons-syndrome/
Team leader: Erwan Bézard
Our goal is to understand molecular and cellular mechanisms responsible for motor and non-motor symptoms in Parkinson’s disease and atypical parkinsonism as well as the disturbed response to L-dopa. Our goal is thus to identify novel therapeutic targets on the ground of pathophysiological studies in experimental models (ranging from cell culture to non-human primate) as well as in man.
The research activities of the team evolve around the following axes:
◦ Mechanisms of cell death in parkinsonian syndromes
◦ Modelling prion-like dissemination of synucleinopathies and tauopathies in nervous system in
Parkinsonian syndromes and dementias.
◦ Study of targeting autophagy as a potential cure of Parkinson’s disease.
◦ Study of key mechanisms contributing to α-synuclein accumulation to counteract Parkinson’s
disease and Multiple System Atrophy progression.
◦ Improvement of transgenesis approaches in neurodegenerative diseases modelling.
◦ Study of the role of extracellular space in neuronal communication.
Modulation of lysosomal biogenesis in experimental models of Parkinson’s disease and L-dopa-induced dyskinesia.

Principal Investigator: Benjamin Dehay, CR2 INSERM, benjamin.dehay@u-bordeaux.fr
Team members, 2016 :
AROTCARENA Marie-Laure (PhD student)
BEZARD Erwan (Researcher)
BOUE-GRABOT Eric (Researcher)
BOURDENX Mathieu (Post-Doctoral fellow)
CANRON Marie-Hélène (Assistant engineer)
CHANSEL Lucie (PhD student)
DEHAY Benjamin (Researcher)
DOVERO Sandra (Study engineer)
DOUDNIKOFF Marie-Evelyne (Assistant engineer)
ESTAGER Alain (Technician)
FERNAGUT Pierre-Olivier (Researcher)
GUERIN Paul-Arnaud (PhD student)
JIMENEZ Clément (PU-PH)
LARGITTE Leslie-Ann (Study engineer)
MARTIN-NEGRIER Marie-Laure (PU-PH)
MARTINEZ Audrey (Assistant engineer)
MASSE Karine (MCU)
MEISSNER Wassilios (PU-PH)
PAMPLIEGA Olatz (Post-Doctoral fellow)
SORIA Federico (Post-Doctoral fellow)
THIOLAT Marie-Laure (Technician)
TISON François (PU-PH)
VITAL Anne (PU-PH)

Keywords: Neurodegenerative diseases, Parkinson’s disease, lysosome, therapy, nanoparticles.

Research Topics

Parkinson’s disease is characterized by a progressive accumulation and propagation of a-synuclein likely responsible for their subsequent death. Our objective is to understand these mechanisms for then proposing adapted therapeutic approaches. Increasing evidence indicates that impairment of autophagy-lysosomal function may contribute to the pathogenesis of Parkinson’s disease. In particular, lysosomal defects could potentially account not only for neuronal cell dysfunction/death, the presence of α-synuclein-containing Lewy bodies, but also for the α-synuclein release from neurons. Our main goal is to understand how the disease proteins cause alterations of the proteolytic pathways contributing to the pathogenesis and, more importantly, whether functional augmentation of the lysosomal pathway can lead to clearance of the toxic proteins and halt the disease process. For this second purpose, we develop new neuroprotective/disease-modifying therapeutic strategies aimed at restoring lysosomal levels and function towards multidimensional clinically-relevant rodent and primate models. In addition to the various research projects, we begin the study of the interaction between autophagy and ciliary machinery in the context of neurodegenerative disease, with a special focus on Alzheimer’s disease.

Legend: Lysosomal dysfunction is a central event in Parkinson’s disease aetiology. Many factors are able, independently or in combination, to induce lysosomal impairment. Consequences of lysosomal impairment are numerous, including proteostasis impairment, ion homeostasis dysregulation, energy homeostasis perturbation or mitochondrial dysfunction. Moreover, several studies have suggested that lysosomal impairment could also promote the progressive spreading of synucleinopathy. All these deleterious consequences of lysosomal impairment are involved in dopaminergic cell death leading to Parkinson’s disease. Lysosomal impairment appears as a self-amplifying deleterious mechanism leading to more profound lysosomal dysfunction. Lysosomal-targeted therapeutic strategies, which have recently emerged, appear as promising therapeutic strategies allowing reversing lysosomal dysfunction.

Legend: Human dopaminergic cells were transfected with LAMP1-GFP to visualize the lysosome (green) before incubation with the nanoparticles PLGA acids containing a red fluorescent dye. Nuclei are stained with Hoechst (blue). Nanoparticles are imported into the cell 15 minutes after the exposure, and inwardly directed lysosome after 24 hours. Acidic nanoparticles appear as discrete points surrounded by LAMP1-GFP signal as observed with this deconvolution of confocal microscopy and image reconstruction in three dimensions associated.

References:

Bourdenx M, Dehay B. Autophagy and brain: specificities and dysfunctions. Med Sci (Paris), volume 33 n°3 (2017).
Bourdenx M, Dehay B. What lysosomes actually tell us about Parkinson’s disease? Ageing Res Rev. 2016 Mar3. pii:S1568-1637(16)30023-X.
Bourdenx M, Daniel J, Genin E, Soria FN, Blanchard-Desce M, Bezard E, Dehay B#. Nanoparticles restore lysosomal acidification defects: Implication for Parkinson’s and other lysosomal-related diseases. Autophagy. 2016 Mar 3;12(3):472-83.
Bourdenx, M., Bezard, E., Dehay, B. Lysosomes and α-synuclein form a dangerous duet leading to neuronal cell death. Front Neuroanat. 2014 Aug 14;8:83.
Bove, J. †, Martinez-Vicente, M. †, Dehay, B. †, Perier, C., Recasens, A., Bombrun, A., Antonsson, B., and Vila, M. Bax channel activity mediates lysosomal disruption linked to Parkinson’s disease. Autophagy. 2014 May;10(5):889-900. († co-first author)
Dehay, B., Martinez-Vicente, M., Caldwell, G., Caldwell, K., Yue, Z., Cookson, M., Klein, C., Vila, M., and Bezard, E. Lysosomal Impairment in Parkinson’s disease. Mov Disorder. 2013 Jun;28(6):725-32.
Dehay, B., Martinez-Vicente, M., Ramirez, A., Perier, C., Klein, C., Vila, M., and Bezard, E. Lysosomal dysfunction in Parkinson disease: ATP13A2 gets into the groove. Autophagy. 2012. Sep;8(9):1389-91.
Dehay, B., Ramirez, A., Martinez-Vicente, M., Perier, C., Canron, MH., Doudnikoff, E., Vital, A., Vila, M., Klein, C., and Bezard, E. Loss of P-type ATPase ATP13A2/PARK9 function induces general lysosomal deficiency and leads to Parkinson disease neurodegeneration. Proc Natl Acad Sci U S A. 2012 Jun 12;109 (24) :9611-6.
Vila, M., Bove, J., Dehay, B., Rodriguez-Muela, C., and Boya, P. Lysosomal membrane permeabilization in Parkinson’s Disease. Autophagy 2011 Jan;7(1):98-100.
Dehay, B., Bove, J., Rodriguez-Muela, C., Perier, C., Recasens, A., Boya, P., and Vila, M. Pathogenic lysosomal depletion in Parkinson’s Disease. J Neurosci. 2010 Sep 15; 30(37): 12535-44.

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