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Early changes induced by ¿-Synuclein in monoamine neurons: new therapeutic strategies for Parkinson's disease

AutorAlarcon, D.; Artigas, Francesc ; Bortolozzi, Analía
Fecha de publicación17-mar-2016
CitaciónECNP Workshop for Junior Scientists (2016)
Resumen[Background] Pathological changes in end-state of Parkinson's disease (PD) are well characterized from postmortem studies. However, there is an urgent need to identify early functional changes ¿ including those responsible for psychiatric symptoms ¿ in order to develop new therapeutic strategies stopping the progression of the illness. Hence, motor symptoms appear after the massive loss (~80%) of dopamine (DA) neurons of the substantia nigra pars compacta (SN). ¿-Synuclein (¿-Syn) is a protein that accumulates in the brain of patients with sporadic PD. Likewise, whole locus multiplications and point mutations in the ¿-Syn gene cause a familial form of PD [1].
[Methods] To better understand the sequence of events occurring in PD, we generated a mouse model overexpressing the human wild-type ¿-Syn in DA neurons from the SN or serotonin (5-HT) neurons from the dorsal and median raphe nuclei (RN). We used an adeno-associated virus type-5 (AAV5)-¿-Syn vector (kindly donated by MJF foundation [2]), which was unilaterally injected into the SN or the RN.
[Results] AAV5-¿-Syn mice showed increased human ¿-Syn mRNA levels in the ipsilateral SN and RN over time reaching 278% and 290% of sham-mice (8 weeks post-infection), whereas endogenous ¿-Syn remained unaltered. Immunohistochemistry analysis confirmed these results and showed an increased level of human ¿-Syn and phospho-¿-Syn levels without a loss of tyrosine hydroxylase- (TH)-positive DA neurons or tryptophan hydroxylase- (TPH2)-positive 5-HT neurons 16 weeks post-injection. In contrast, the increased expression of human ¿-Syn was paralleled by (1) an impaired release of DA and 5-HT, and (2) the swelling of ¿-Syn-positive axons in various forebrain areas (e.g., striatum, hippocampus and cerebral cortex) 4 weeks after injection. Hence, local perfusion by reverse dialysis of the depolarizing agent veratridine (50 ¿M) decreased DA and 5-HT release in the striatum of AAV5-¿-Syn mice injected in SN or RN, respectively. In addition, the effects of DA and 5-HT reuptake inhibitors nomifensine (1¿10¿50 ¿M) and citalopram (1¿10¿50 ¿M), respectively, on striatal DA or 5-HT levels were deeply reduced in AAV5-¿-Syn versus sham mice compared to controls. Moreover, mice injected with AAV5-¿-Syn in the SN showed motor impairments at 8 weeks post-infection and those injected in the RN showed depressive-like behaviors (tail suspension and forced swim tests) at 4 weeks post-infection. Intranasal treatment (23 days) with an indatraline-conjugated antisense oligonucleotide, designed to selectively target DA and 5-HT neurons (ASO1233), reduced ¿-synuclein expression in both midbrain nuclei.
[Conclusions] ¿-synuclein acts as a negative modulator of DA and 5-HT neurotransmission, altering axonal morphology and reducing physiological monoamine release, an effect that may underlie early symptoms of PD, including mood and anxiety disorders. Synaptic DA and 5-HT dysfunctions and axonopathies would thus be hallmarks of early-stage PD and suggest that ASO targeting of ¿-synuclein in monoamine neurons may be a new therapeutic strategy for PD.
DescripciónTrabajo presentado en el ECNP Workshop for Junior Scientists, celebrado en Miza, Francia, del 17 al 20 de marzo de 2016
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