Lack of additive role of ageing in nigrostriatal neurodegeneration triggered by α-synuclein overexpression.
acta neuropathol commun. 2015-07-25; 3(1):
Read on PubMed
1. Acta Neuropathol Commun. 2015 Jul 25;3:46. doi: 10.1186/s40478-015-0222-2.
Lack of additive role of ageing in nigrostriatal neurodegeneration triggered by
Bourdenx M(1)(2), Dovero S(1)(2), Engeln M(1)(2), Bido S(1)(2), Bastide MF(1)(2),
Dutheil N(1)(2), Vollenweider I(3), Baud L(3), Piron C(1)(2), Grouthier V(1)(2),
Boraud T(1)(2), Porras G(4), Li Q(4)(5), Baekelandt V(6), Scheller D(7), Michel
A(7), Fernagut PO(1)(2), Georges F(8)(9), Courtine G(3), Bezard E(10)(11), Dehay
(1)University de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293,
33000, Bordeaux, France.
(2)CNRS, Institut des Maladies Neurodégénératives, UMR 5293, 33000, Bordeaux,
(3)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.
(4)Motac Neuroscience, Manchester, UK.
(5)Institute of Laboratory Animal Sciences, China Academy of Medical Sciences,
(6)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.
(7)Parkinson’s Disease Pharmacology, UCB Pharma S.A., Braine L’Alleud, B-1420,
(8)University de Bordeaux, Interdisciplinary Institute for Neuroscience, UMR5297,
(9)CNRS, Institut Interdisciplinaire de Neurosciences, UMR 5297, F-33000,
(10)University de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293,
33000, Bordeaux, France. .
(11)CNRS, Institut des Maladies Neurodégénératives, UMR 5293, 33000, Bordeaux,
(12)University de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293,
33000, Bordeaux, France. .
(13)CNRS, Institut des Maladies Neurodégénératives, UMR 5293, 33000, Bordeaux,
INTRODUCTION: 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
PMID: 26205255 [Indexed for MEDLINE]