Mathieu Bourdenx & Benjamin Dehay dans Acta Neuro

Lack of additive role of ageing in nigrostriatal neurodegeneration triggered by α-synuclein overexpression.
 Bourdenx M, Dovero S, Engeln M, Bido S, Bastide MF, Dutheil N, Vollenweider I, Baud L, Piron C, Grouthier V, Boraud T, Porras G, Li Q, Baekelandt V, Scheller D, Michel A, Fernagut PO, Georges F, Courtine G, Bezard E, Dehay B.
Acta Neuropathol Commun. 2015 Jul 25;3(1):46. doi: 10.1186/s40478-015-0222-2.

α-Synuclein has a unique importance in the aetiology of Parkinson’s disease (PD), as it appears to link familial and sporadic forms of the human disease (Dehay et al., Lancet Neurology 2015). To date, several α-synuclein-transgenic animal models for PD have been developed although none of them represent the full clinical picture of PD: progressive and specific DA cell loss, protein aggregation and PD-like symptoms.
Later on, the development of recombinant adeno-associated virus (rAAV) has opened up new possibilities regarding PD modelling. Nevertheless, the literature reports a bewildering variety of vectors, expression cassettes, serotypes, and titers preventing a clear comparison between results, strains and species. There was thus a need for a detailed analysis of the dynamics and functional implications of the α-syn-related neurodegeneration response, in order to better understand this complex pathology. A comprehensive multi-hit approach is required to model PD neurodegeneration.
Of importance, ageing remains the most prominent risk factor for developing PD. However, the impact of ageing has been largely overlooked in preclinical studies of PD. In this study, we investigated the influence of ageing on the dynamics of PD-related neurodegeneration associated with α-syn pathology in a series of mammalian species in a new AAV-based framework.

Our results indicate that AAV of pseudotype 9-mediated overexpression of human mutant p.A53T α-syn induces neurodegeneration and synucleinopathy in mice, rats and monkeys, with motor dysfunctions reminiscent of PD in rats.
Interestingly, species diverge vis-à-vis their α-syn phosphorylation status, as monkeys do not present a correlation between levels of phosphorylated α-syn and neurodegeneration.

Most importantly, we demonstrate that ageing does not influence α-syn-induced nigrostriatal neurodegeneration nor α-syn pathology per se but simply adds to the α-syn overexpression (Bourdenx et al., 2015).
On the basis of our results, we favour the multiple-hit hypothesis for PD with ageing being an aggravating factor superimposing upon the disease process.