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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
URIhttp://hdl.handle.net/10261/147347
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