21-07-08(19:17:55)
Authors:
Bernard L. Schneider
Meret N. Gaugler
Samareh Azeredo da Silveira Lajaunias
Jean-Charles Bensadoun
Patrick Aebischer
Institutions:
Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
Title of abstract : Viral vectors for modeling and treating Parkinson disease
Abstract text:
In order to develop effective neuroprotective strategies for Parkinson disease (PD), it appears essential to understand the interplay between multiple genes involved in familial forms of the disease, aging and environmental factors. The use of viral vectors to locally deliver pathogenic genes, such as α-synuclein, offers an effective means to analyze how genetic perturbations of neuronal homeostasis can affect adult nigral dopaminergic neurons.
Using lentiviral and, more recently, adeno-associated vectors, we have induced over-expression of human α-synuclein in the rat substantia nigra (SNpc) and assessed the resulting histopathological and behavioral impact. In order to determine primary pathogenic events, we have used a range of viral doses inducing a mild loss of dopaminergic markers (20-40%) over the course of three months. In spite of this sub-acute lesion, unilateral over-expression of wild-type α-synuclein induces a significant asymmetry in spontaneous motor behavior. This effect is reflected by a 65% decrease in evoked dopamine release at the striatal level, which exceeds the loss of dopaminergic markers. This suggests direct functional effects of α-synuclein accumulation that may precede neuronal loss.
By modifying the amino acid sequence of α synuclein, we have determined whether phosphorylation at serine 129 impacts the histopathological alterations when over-expressed in the SNpc. Serine replacement by an alanine residue (S129A), which prevents phosphorylation, favors the accumulation of Thioflavin-stained structures in the injected SNpc and enhances the loss of dopaminergic markers. Incorporation of an aspartate residue (S129D) mimicking phosphorylation attenuates the pathologic effects of α-synuclein.
By deciphering the functional and histopathological consequences of α-synuclein over-expression in the mammalian nigrostriatal system, these results provide crucial insights into early pathogenesis of both familial and sporadic forms of PD.
