Cargando…

Lack of additive role of ageing in nigrostriatal neurodegeneration triggered by α-synuclein overexpression

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Bourdenx, Mathieu, Dovero, Sandra, Engeln, Michel, Bido, Simone, Bastide, Matthieu F., Dutheil, Nathalie, Vollenweider, Isabel, Baud, Laetitia, Piron, Camille, Grouthier, Virginie, Boraud, Thomas, Porras, Grégory, Li, Qin, Baekelandt, Veerle, Scheller, Dieter, Michel, Anne, Fernagut, Pierre-Olivier, Georges, François, Courtine, Grégoire, Bezard, Erwan, Dehay, Benjamin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4513748/
https://www.ncbi.nlm.nih.gov/pubmed/26205255
http://dx.doi.org/10.1186/s40478-015-0222-2
_version_ 1782382686164221952
author Bourdenx, Mathieu
Dovero, Sandra
Engeln, Michel
Bido, Simone
Bastide, Matthieu F.
Dutheil, Nathalie
Vollenweider, Isabel
Baud, Laetitia
Piron, Camille
Grouthier, Virginie
Boraud, Thomas
Porras, Grégory
Li, Qin
Baekelandt, Veerle
Scheller, Dieter
Michel, Anne
Fernagut, Pierre-Olivier
Georges, François
Courtine, Grégoire
Bezard, Erwan
Dehay, Benjamin
author_facet Bourdenx, Mathieu
Dovero, Sandra
Engeln, Michel
Bido, Simone
Bastide, Matthieu F.
Dutheil, Nathalie
Vollenweider, Isabel
Baud, Laetitia
Piron, Camille
Grouthier, Virginie
Boraud, Thomas
Porras, Grégory
Li, Qin
Baekelandt, Veerle
Scheller, Dieter
Michel, Anne
Fernagut, Pierre-Olivier
Georges, François
Courtine, Grégoire
Bezard, Erwan
Dehay, Benjamin
author_sort Bourdenx, Mathieu
collection PubMed
description 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 disease process. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40478-015-0222-2) contains supplementary material, which is available to authorized users.
format Online
Article
Text
id pubmed-4513748
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-45137482015-07-25 Lack of additive role of ageing in nigrostriatal neurodegeneration triggered by α-synuclein overexpression Bourdenx, Mathieu Dovero, Sandra Engeln, Michel Bido, Simone Bastide, Matthieu F. Dutheil, Nathalie Vollenweider, Isabel Baud, Laetitia Piron, Camille Grouthier, Virginie Boraud, Thomas Porras, Grégory Li, Qin Baekelandt, Veerle Scheller, Dieter Michel, Anne Fernagut, Pierre-Olivier Georges, François Courtine, Grégoire Bezard, Erwan Dehay, Benjamin Acta Neuropathol Commun Research 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 disease process. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40478-015-0222-2) contains supplementary material, which is available to authorized users. BioMed Central 2015-07-25 /pmc/articles/PMC4513748/ /pubmed/26205255 http://dx.doi.org/10.1186/s40478-015-0222-2 Text en © Bourdenx et al. 2015 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Bourdenx, Mathieu
Dovero, Sandra
Engeln, Michel
Bido, Simone
Bastide, Matthieu F.
Dutheil, Nathalie
Vollenweider, Isabel
Baud, Laetitia
Piron, Camille
Grouthier, Virginie
Boraud, Thomas
Porras, Grégory
Li, Qin
Baekelandt, Veerle
Scheller, Dieter
Michel, Anne
Fernagut, Pierre-Olivier
Georges, François
Courtine, Grégoire
Bezard, Erwan
Dehay, Benjamin
Lack of additive role of ageing in nigrostriatal neurodegeneration triggered by α-synuclein overexpression
title Lack of additive role of ageing in nigrostriatal neurodegeneration triggered by α-synuclein overexpression
title_full Lack of additive role of ageing in nigrostriatal neurodegeneration triggered by α-synuclein overexpression
title_fullStr Lack of additive role of ageing in nigrostriatal neurodegeneration triggered by α-synuclein overexpression
title_full_unstemmed Lack of additive role of ageing in nigrostriatal neurodegeneration triggered by α-synuclein overexpression
title_short Lack of additive role of ageing in nigrostriatal neurodegeneration triggered by α-synuclein overexpression
title_sort lack of additive role of ageing in nigrostriatal neurodegeneration triggered by α-synuclein overexpression
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4513748/
https://www.ncbi.nlm.nih.gov/pubmed/26205255
http://dx.doi.org/10.1186/s40478-015-0222-2
work_keys_str_mv AT bourdenxmathieu lackofadditiveroleofageinginnigrostriatalneurodegenerationtriggeredbyasynucleinoverexpression
AT doverosandra lackofadditiveroleofageinginnigrostriatalneurodegenerationtriggeredbyasynucleinoverexpression
AT engelnmichel lackofadditiveroleofageinginnigrostriatalneurodegenerationtriggeredbyasynucleinoverexpression
AT bidosimone lackofadditiveroleofageinginnigrostriatalneurodegenerationtriggeredbyasynucleinoverexpression
AT bastidematthieuf lackofadditiveroleofageinginnigrostriatalneurodegenerationtriggeredbyasynucleinoverexpression
AT dutheilnathalie lackofadditiveroleofageinginnigrostriatalneurodegenerationtriggeredbyasynucleinoverexpression
AT vollenweiderisabel lackofadditiveroleofageinginnigrostriatalneurodegenerationtriggeredbyasynucleinoverexpression
AT baudlaetitia lackofadditiveroleofageinginnigrostriatalneurodegenerationtriggeredbyasynucleinoverexpression
AT pironcamille lackofadditiveroleofageinginnigrostriatalneurodegenerationtriggeredbyasynucleinoverexpression
AT grouthiervirginie lackofadditiveroleofageinginnigrostriatalneurodegenerationtriggeredbyasynucleinoverexpression
AT boraudthomas lackofadditiveroleofageinginnigrostriatalneurodegenerationtriggeredbyasynucleinoverexpression
AT porrasgregory lackofadditiveroleofageinginnigrostriatalneurodegenerationtriggeredbyasynucleinoverexpression
AT liqin lackofadditiveroleofageinginnigrostriatalneurodegenerationtriggeredbyasynucleinoverexpression
AT baekelandtveerle lackofadditiveroleofageinginnigrostriatalneurodegenerationtriggeredbyasynucleinoverexpression
AT schellerdieter lackofadditiveroleofageinginnigrostriatalneurodegenerationtriggeredbyasynucleinoverexpression
AT michelanne lackofadditiveroleofageinginnigrostriatalneurodegenerationtriggeredbyasynucleinoverexpression
AT fernagutpierreolivier lackofadditiveroleofageinginnigrostriatalneurodegenerationtriggeredbyasynucleinoverexpression
AT georgesfrancois lackofadditiveroleofageinginnigrostriatalneurodegenerationtriggeredbyasynucleinoverexpression
AT courtinegregoire lackofadditiveroleofageinginnigrostriatalneurodegenerationtriggeredbyasynucleinoverexpression
AT bezarderwan lackofadditiveroleofageinginnigrostriatalneurodegenerationtriggeredbyasynucleinoverexpression
AT dehaybenjamin lackofadditiveroleofageinginnigrostriatalneurodegenerationtriggeredbyasynucleinoverexpression