English   español  
Por favor, use este identificador para citar o enlazar a este item: http://hdl.handle.net/10261/147347
logo share SHARE   Add this article to your Mendeley library MendeleyBASE
Visualizar otros formatos: MARC | Dublin Core | RDF | ORE | MODS | METS | DIDL
Exportar a otros formatos:

Antisense oligonucleotide reduction of human alpha-synuclein accumulation in dopamine and serotonin neurons prevents early dysfunctions in a mouse model of Parkinson's disease

AutorAlarcon, D.; Ruiz-Bronchal, Esther; Artigas, Francesc ; Bortolozzi, Analía
Fecha de publicación12-nov-2016
CitaciónNeuroscience 2016
ResumenMultiple convergent lines of evidence implicate ¿-synuclein (encoded by SCNA) in the pathogenic of Parkinson¿s disease (PD). ¿-Synuclein is a protein that accumulates in the brain of patients with sporadic PD. Likewise, whole locus multiplications and point mutations in the ¿-synuclein gene cause a familial form of PD. Previously, we developed a mouse model that overexpress wild-type human-¿-synuclein in the AAV5 vector (donated by MJF foundation) in dopamine (DA) neurons of the substantia nigra compacta (SNc) and ventral tegmental area (VTA) as well as in serotonin (5-HT) neurons of the raphe nuclei (RN). These mice showed increased human-¿-synuclein mRNA levels in the ipsilateral SNc (278% of sham mice) and RN (290% of sham mice), but they did not display any loss of tyrosine hydroxylase-positive DA neurons or tryptophan hydroxylase-positive 5-HT neurons at 16 weeks post-injection. Moreover, reduced DA and 5-HT release paralleled with development of ¿-synuclein-positive axonal swelling in striatum, hippocampus and cerebral cortex were found in the AAV5 model. In addition, AAV5 mice exhibited motor deficits at 8 weeks post-infection into SN and depressive-like behaviors (tail suspension and forced swim tests) at 4 weeks post-infection into RN. Here, we evaluated whether reducing human ¿-synuclein expression in the mesencephalic nuclei prevented early dysfunctions in the AAV5 model. We used a conjugated antisense oligonucleotide targeting intracellular human ¿-synuclein (ASO1337) selectively in DA and 5-HT neurons. Mice overexpressing human ¿-synuclein in the SNc/VTA or RN were treated intracerebroventricularly with ASO1337 (30 or 100¿g/day) during 28 days using osmotic minipumps implanted subcutaneously. Control groups received vehicle or nonsense ASO sequence (ASO1227) in the same conditions. ASO1337 reduced dose-dependent the human ¿-synuclein mRNA levels (vehicle: 0.76±0.04; ASO1337 30¿g/day: 0.46±0.05; ASO1337 100¿/day: 0.35±0.03, arbitrary units), whereas endogenous ¿-synuclein and ¿-synuclein expression remained unaltered. Immunohistochemistry analysis confirmed these results showing the reduction of human ¿-synuclein protein density. Furthermore, recovery of striatal DA release could be achieved by reduction of human-¿-synuclein expression in SNc/VTA. Recent data showed that intracerebroventricular ASO1337 infusion (100¿g/day, 28 days) also decreased human ¿-synuclein mRNA expression in the RN of AAV5 mice compared to control groups. Our study indicated that the ASO-induced reduction of intracellular ¿-synuclein accumulation selectively in DA and 5-HT neurons using ASO molecules represents an optimal PD therapy.
DescripciónTrabajo presentado en Neuroscience 2016, celebrado en San diego, California, del 12 al 16 de noviembre de 2016
Aparece en las colecciones: (IIBB) Comunicaciones congresos
Ficheros en este ítem:
Fichero Descripción Tamaño Formato  
accesoRestringido.pdf15,38 kBAdobe PDFVista previa
Mostrar el registro completo

NOTA: Los ítems de Digital.CSIC están protegidos por copyright, con todos los derechos reservados, a menos que se indique lo contrario.