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Ann Neurol:研究发现帕金森氏病发生发展的新机制

来源:生物谷 2014-04-12 09:35

2014年4月11日讯 /生物谷BIOON/--近日,Research Institute Vall d'Hebron (VHIR)科学家领导的一项研究表明:存在于帕金森氏症死亡患者大脑中的病理形态α-突触核蛋白,能够在老鼠和灵长类动物中发起和传播神经退化过程。这一发现发表在Annals of Neurology杂志上,打开阻止帕金森氏病进展,阻断α-突触核蛋白的表达,抑制这种蛋白质传播,以及开发新治疗方法的大门。

最近的研究表明,α-突触核蛋白的合成形式是神经毒性的,无论是在体外(细胞培养)和体内(小鼠),它可以从一个细胞传播到另一个细胞。然而,直到现在人们不知道这种致病蛋白质合成能力是否与帕金森氏患者大脑中病理性蛋白质有关。

在本研究中, Miquel Vila医生等研究人员从帕金森氏症死亡患者大脑中提取α-突触核蛋白聚合体,将它们注入啮齿动物和灵长类动物的大脑。在注射到小鼠体内四个月后,注射入猴子九个月后,这些动物开始呈现多巴胺能神经元变性和α-突触核蛋白病理聚集(如发生帕金森氏病一样)。数个月后,动物也表现出大脑中其他偏远部位蛋白质的聚集,类似毒性蛋白的传播(如在患者经过多年疾病演变后大脑中观察到的格局)。

这些结果表明,从帕金森氏症患者获得的该蛋白质病理学聚集体具有在小鼠和灵长类动物发起和促发神经变性过程的能力,这提供了关于本病启动发生和发展机制的新见解,并打开发现新治疗机会的大门。

帕金森氏病是阿尔茨海默病之后的第二最常见的神经变性疾病。因此,下一步是找出如何停止疾病进展和毒性蛋白的传播。(生物谷Bioon.com)

 

doi:10.1002/ana.24066
Lewy body extracts from Parkinson disease brains trigger α-synuclein pathology and neurodegeneration in mice and monkeys

Ariadna Recasens, Benjamin Dehay, Jordi Bové, Iria Carballo-Carbajal, Sandra Dovero, Ana Pérez-Villalba, Pierre-Olivier Fernagut, Javier Blesa, Annabelle Parent, Celine Perier, Isabel Fari?as, José A. Obeso, Erwan Bezard and Miquel Vila.

Objective
Mounting evidence suggests that α-synuclein, a major protein component of Lewy bodies (LB), may be responsible for initiating and spreading the pathological process in Parkinson disease (PD). Supporting this concept, intracerebral inoculation of synthetic recombinant α-synuclein fibrils can trigger α-synuclein pathology in mice. However, it remains uncertain whether the pathogenic effects of recombinant synthetic α-synuclein may apply to PD-linked pathological α-synuclein and occur in species closer to humans.

Methods
Nigral LB-enriched fractions containing pathological α-synuclein were purified from postmortem PD brains by sucrose gradient fractionation and subsequently inoculated into the substantia nigra or striatum of wild-type mice and macaque monkeys. Control animals received non-LB fractions containing soluble α-synuclein derived from the same nigral PD tissue.

Results
In both mice and monkeys, intranigral or intrastriatal inoculations of PD-derived LB extracts resulted in progressive nigrostriatal neurodegeneration starting at striatal dopaminergic terminals. No neurodegeneration was observed in animals receiving non-LB fractions from the same patients. In LB-injected animals, exogenous human α-synuclein was quickly internalized within host neurons and triggered the pathological conversion of endogenous α-synuclein. At the onset of LB-induced degeneration, host pathological α-synuclein diffusely accumulated within nigral neurons and anatomically interconnected regions, both anterogradely and retrogradely. LB-induced pathogenic effects required both human α-synuclein present in LB extracts and host expression of α-synuclein.

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