title: Lack of additive role of ageing in nigrostriatal neurodegeneration triggered by α-synuclein overexpression.
abstract: BACKGROUND
  Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons as well as the presence of proteinaceous inclusions named Lewy bodies. α-synuclein (α-syn) is a major constituent of Lewy bodies, and the first disease-causing protein characterized in PD. Several α-syn-based animal models of PD have been developed to investigate the pathophysiology of PD, but none of them recapitulate the full picture of the disease. Ageing is the most compelling and major risk factor for developing PD but its impact on α-syn toxicity remains however unexplored. In this study, we developed and exploited a recombinant adeno-associated viral (AAV) vector of serotype 9 overexpressing mutated α-syn to elucidate the influence of ageing on the dynamics of PD-related neurodegeneration associated with α-syn pathology in different mammalian species.
  
  
  RESULTS
  Identical AAV pseudotype 2/9 vectors carrying the DNA for human mutant p.A53T α-syn were injected into the substantia nigra to induce neurodegeneration and synucleinopathy in mice, rats and monkeys. Rats were used first to validate the ability of this serotype to replicate α-syn pathology and second to investigate the relationship between the kinetics of α-syn-induced nigrostriatal degeneration and the progressive onset of motor dysfunctions, strikingly reminiscent of the impairments observed in PD patients. In mice, AAV2/9-hα-syn injection into the substantia nigra was associated with accumulation of α-syn and phosphorylated hα-syn, regardless of mouse strain. However, phenotypic mutants with either accelerated senescence or resistance to senescence did not display differential susceptibility to hα-syn overexpression. Of note, p-α-syn levels correlated with nigrostriatal degeneration in mice. In monkeys, hα-syn-induced degeneration of the nigrostriatal pathway was not affected by the age of the animals. Unlike mice, monkeys did not exhibit correlations between levels of phosphorylated α-syn and neurodegeneration.
  
  
  CONCLUSIONS
  In conclusion, AAV2/9-mediated hα-syn induces robust nigrostriatal neurodegeneration in mice, rats and monkeys, allowing translational comparisons among species. Ageing, however, neither exacerbated nigrostriatal neurodegeneration nor α-syn pathology per se. Our unprecedented multi-species investigation thus favours the multiple-hit hypothesis for PD wherein ageing would merely be an aggravating, additive, factor superimposed upon an independent disease process.
authors.affiliation: University de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, 33000, Bordeaux, France.|CNRS, Institut des Maladies Neurodégénératives, UMR 5293, 33000, Bordeaux, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Bourdenx
authors.affiliation: University de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, 33000, Bordeaux, France.|CNRS, Institut des Maladies Neurodégénératives, UMR 5293, 33000, Bordeaux, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Dovero
authors.affiliation: University de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, 33000, Bordeaux, France.|CNRS, Institut des Maladies Neurodégénératives, UMR 5293, 33000, Bordeaux, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Engeln
authors.affiliation: University de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, 33000, Bordeaux, France.|CNRS, Institut des Maladies Neurodégénératives, UMR 5293, 33000, Bordeaux, France.
authors.forename: Simone
authors.initials: S
authors.lastname: Bido
authors.affiliation: University de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, 33000, Bordeaux, France.|CNRS, Institut des Maladies Neurodégénératives, UMR 5293, 33000, Bordeaux, France.
authors.forename: Matthieu F
authors.initials: MF
authors.lastname: Bastide
authors.affiliation: University de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, 33000, Bordeaux, France.|CNRS, Institut des Maladies Neurodégénératives, UMR 5293, 33000, Bordeaux, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dutheil
authors.affiliation: International Paraplegic Foundation chair in spinal cord Repair, Center for Neuroprosthetics and Brain Mind Institute, School of Life Sciences, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland.
authors.forename: Isabel
authors.initials: I
authors.lastname: Vollenweider
authors.affiliation: International Paraplegic Foundation chair in spinal cord Repair, Center for Neuroprosthetics and Brain Mind Institute, School of Life Sciences, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Baud
authors.affiliation: University de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, 33000, Bordeaux, France.|CNRS, Institut des Maladies Neurodégénératives, UMR 5293, 33000, Bordeaux, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Piron
authors.affiliation: University de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, 33000, Bordeaux, France.|CNRS, Institut des Maladies Neurodégénératives, UMR 5293, 33000, Bordeaux, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Grouthier
authors.affiliation: University de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, 33000, Bordeaux, France.|CNRS, Institut des Maladies Neurodégénératives, UMR 5293, 33000, Bordeaux, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Boraud
authors.affiliation: Motac Neuroscience, Manchester, UK.
authors.forename: Grégory
authors.initials: G
authors.lastname: Porras
authors.affiliation: Motac Neuroscience, Manchester, UK.|Institute of Laboratory Animal Sciences, China Academy of Medical Sciences, Beijing, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Neurosciences and Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven, Laboratory for Neurobiology and Gene Therapy, Kapucijnenvoer 33, box 7001, 3000, Leuven, Belgium.
authors.forename: Veerle
authors.initials: V
authors.lastname: Baekelandt
authors.affiliation: Parkinson's Disease Pharmacology, UCB Pharma S.A., Braine L'Alleud, B-1420, Belgium.
authors.forename: Dieter
authors.initials: D
authors.lastname: Scheller
authors.affiliation: Parkinson's Disease Pharmacology, UCB Pharma S.A., Braine L'Alleud, B-1420, Belgium.
authors.forename: Anne
authors.initials: A
authors.lastname: Michel
authors.affiliation: University de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, 33000, Bordeaux, France.|CNRS, Institut des Maladies Neurodégénératives, UMR 5293, 33000, Bordeaux, France.
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Fernagut
authors.affiliation: University de Bordeaux, Interdisciplinary Institute for Neuroscience, UMR5297, Bordeaux, France.|CNRS, Institut Interdisciplinaire de Neurosciences, UMR 5297, F-33000, Bordeaux, France.
authors.forename: François
authors.initials: F
authors.lastname: Georges
authors.affiliation: International Paraplegic Foundation chair in spinal cord Repair, Center for Neuroprosthetics and Brain Mind Institute, School of Life Sciences, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland.
authors.forename: Grégoire
authors.initials: G
authors.lastname: Courtine
authors.affiliation: University de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, 33000, Bordeaux, France. erwan.bezard@u-bordeaux.fr.|CNRS, Institut des Maladies Neurodégénératives, UMR 5293, 33000, Bordeaux, France. erwan.bezard@u-bordeaux.fr.
authors.forename: Erwan
authors.initials: E
authors.lastname: Bezard
authors.affiliation: University de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, 33000, Bordeaux, France. benjamin.dehay@u-bordeaux.fr.|CNRS, Institut des Maladies Neurodégénératives, UMR 5293, 33000, Bordeaux, France. benjamin.dehay@u-bordeaux.fr.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Dehay
mesh_terms: D000375:Aging; D000818:Animals; D001696:Biomechanical Phenomena; D002144:Callithrix; D004195:Disease Models, Animal; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020267:MPTP Poisoning / Q000139:chemically induced / Q000473:pathology*; D051379:Mice; D009043:Motor Activity; D025341:Principal Component Analysis; D011597:Psychomotor Performance / Q000502:physiology; D051381:Rats; D020955:Striatonigral Degeneration / Q000209:etiology / Q000473:pathology*; D013378:Substantia Nigra / Q000378:metabolism*; D013997:Time Factors; D014161:Transduction, Genetic; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D051844:alpha-Synuclein; D049452:Green Fluorescent Proteins; D014446:Tyrosine 3-Monooxygenase