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Nat Neurosci.:科学家揭示LRRK2引起帕金森氏病的机制

来源:生物谷 2013-03-04 17:09

2013年3月4日讯 /生物谷BIOON/--Yeshiva大学爱因斯坦学院科学家在发表在近期Nature Neuroscience的文章,发现了家族性帕金森氏病中常见遗传突变如何破坏神经元的机制。该文章为治疗家族性和散发性帕金森氏病提供了指导作用。

帕金森氏病是一种进行性神经系统疾病,引起震颤和运动缓慢。最常见的家族性PD突变体是影响leucine-rich repeat kinase-2 (LRRK2) 基因。突变引起LRRK2基因编码出异常LRRK2蛋白。但是LRRK2突变体如何导致诸如多巴胺神经元内异常蛋白聚合物形成等PD显微标志还未知晓。

爱因斯坦学院发育和分子生物学系教授Ana Maria Cuervo博士称,我们的研究发现LRRK2的异常形式能够破坏细胞内垃圾蛋白处理过程,该过程正常情况下能够降解并循环使用多余蛋白,如PD病人神经元内蛋白聚合物中的重要成分alpha-synuclein。该垃圾蛋白处理过程称之为chaperone介导的自嗜过程。特殊分子指导陈旧的或遭到破坏的蛋白到溶酶体结构中,该结构包含大量的酶,能够将蛋白质降解为氨基酸,循环入细胞内可以进行再利用。

Cuervo博士称,我们发现LRRK2抑制chaperone介导的自嗜过程后,alpha-synuclein不能被降解,从而在神经元中聚集,产生毒性。

研究人呢有使用了不同模型来证明该发现,如培养的小鼠神经元细胞,具有LRRK2突变的PD病人的神经元,通过iPS技术将PD病人皮肤转化而来的神经元等。

Cuervo博士称,我们在寻找能够增强自嗜过程的方法,看是否能够预防或者延缓神经元的死亡。初步尝试了一些药物,成效很显著。

Cuervo博士希望该治疗能够帮助家族性或者散发性PD病人,特别是由于alpha-synuclein引起的PD。(生物谷Bioon.com)

Interplay of LRRK2 with chaperone-mediated autophagy

Samantha J Orenstein, Sheng-Hang Kuo,Inmaculada Tasset, Esperanza Arias, Hiroshi Koga, Irene Fernandez-Carasa, Etty Cortes, Lawrence S Honig, William Dauer, Antonella Consiglio, Angel Raya, David Sulzer, Ana Maria Cuervo

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease. We found LRRK2 to be degraded in lysosomes by chaperone-mediated autophagy (CMA), whereas the most common pathogenic mutant form of LRRK2, G2019S, was poorly degraded by this pathway. In contrast to the behavior of typical CMA substrates, lysosomal binding of both wild-type and several pathogenic mutant LRRK2 proteins was enhanced in the presence of other CMA substrates, which interfered with the organization of the CMA translocation complex, resulting in defective CMA. Cells responded to such LRRK2-mediated CMA compromise by increasing levels of the CMA lysosomal receptor, as seen in neuronal cultures and brains of LRRK2 transgenic mice, induced pluripotent stem cell¨Cderived dopaminergic neurons and brains of Parkinson's disease patients with LRRK2 mutations. This newly described LRRK2 self-perpetuating inhibitory effect on CMA could underlie toxicity in Parkinson's disease by compromising the degradation of ¦Á-synuclein, another Parkinson's disease¨Crelated protein degraded by this pathway.

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