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Early Functional Changes Induced by Overexpression of ¿-Synuclein in Mouse Dopamine and Serotonin Neurons: New Therapeutic Approaches using Antisense Oligonucleotides

AutorAlarcon, D.; Galofré, Mireia ; Ruiz-Bronchal, Esther; Ferrés-Coy, Albert ; Artigas, Francesc ; Bortolozzi, Analía
Fecha de publicación2-jul-2016
Citación10th FENS Forum of Neuroscience (2016)
ResumenPathological changes in end-state of Parkinson¿s disease (PD) are well characterized. However, there is an urgent need to identify early functional changes to develop new therapeutic strategies stopping the development of the illness. ¿-Synuclein is a protein accumulating in the brain of PD patients. To better understand the sequence of events occurring in PD, we generated a mouse model overexpressing wild-type human-¿-synuclein in dopamine-DA or serotonin-5-HT neurons of substantia nigra (SN) and raphe nuclei (RN), respectively. We used an adeno-associated virus type-5 (AAV5)-¿-synuclein vector, unilaterally injected in SN or RN. AAV5-¿-synuclein mice showed increased human-¿-synuclein mRNA levels in the ipsilateral SN and RN (278 and 290% of sham mice, respectively, 8-week post-infection), without changes of endogenous ¿-synuclein. Immunohistochemistry analysis revealed increased human-¿-synuclein and phospho-¿-synuclein levels; but, the mice did not display any loss of tyrosine hydroxylase-(TH)-positive or tryptophan hydroxylase-(TPH2)-positive neurons. However, impairments in DA or 5-HT release paralleled with development of ¿-synuclein-positive axonal swelling in forebrain were found. Veratridine perfusion (50¿M) decreased DA and 5-HT release in the striatum of AAV5-¿-synuclein mice. Likewise, nomifensine (1-10-50¿M) or citalopram (1-10-50¿M) reduced striatal DA or 5-HT levels, respectively, in AAV5-¿-synuclein versus sham mice. Moreover, these mice displayed motor impairments and depressive-like behaviors. Intranasal treatment (30 days) with a conjugated antisense oligonucleotide (ASO) targeting human-¿-synuclein reduced ¿-synuclein expression selectively in monoamine neurons. Synaptic DA and 5-HT dysfunctions and axonopathy would thus be the hallmark of early-stage of PD and suggest that ASO targeted ¿-synuclein in monoamine neurons may lead to new therapies for PD.
DescripciónTrabajo presentado en el 10th FENS Forum of Neuroscience (FENS 2016), celebrado en Copenhague, Dinamarca, del 2 al 6 de julio de 2016
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