A familial ATP13A2 mutation enhances alpha-synuclein aggregation and promotes cell death
A familial ATP13A2 mutation enhances alpha-synuclein aggregation and promotes cell death
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DOI：
10.1093/hmg/ddw147
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发表时间：
2016-07-15
影响因子：
3.5
通讯作者：
Outeiro, Tiago F.
中科院分区：
文献类型：
--
作者：
da Fonseca, Tomas Lopes;Pinho, Raquel;Outeiro, Tiago F.
异常的蛋白质-蛋白质相互作用是神经退行性疾病（包括帕金森病（PD））中的常见病理标志。到目前为止，超过20个基因的突变与PD相关。这些基因编码参与不同细胞内途径的蛋白质，使我们对疾病背后的精确分子机制的理解变得复杂。最近的报道表明，内溶酶体蛋白ATP 13 A2可以决定α-突触核蛋白（α-Syn）的命运，尽管尚未就这种作用的机制达成共识。在这里，我们描述，第一次，从ATP 13 A2家族突变体Dup 22与α-Syn之间的相互作用所产生的有害影响。我们表明，这种ATP 13 A2突变体可以增强细胞培养物中的α-Syn寡聚化和聚集。此外，我们报告了这两种蛋白质在异常内质网膜结构中的积累和蛋白激酶RNA样内质网激酶途径的激活。最终，我们的数据为这两种蛋白质相互作用的分子机制带来了新的见解，为治疗干预开辟了新的视角。
Aberrant protein-protein interactions are a common pathological hallmark among neurodegenerative diseases, including Parkinson's disease (PD). Thus far, mutations in more than 20 genes have been associated with PD. These genes encode for proteins involved in distinct intracellular pathways, complicating our understanding of the precise molecular mechanisms underlying the disease. Recent reports suggested that the endolysosomal protein ATP13A2 can determine the fate of alpha-synuclein (alpha-Syn), although no consensus has yet been reached on the mechanisms underlying this effect. Here, we describe, for the first time, the deleterious effect arising from the interaction between the ATP13A2 familial mutant Dup22 with alpha-Syn. We show that this ATP13A2 mutant can enhance a-Syn oligomerization and aggregation in cell culture. Additionally, we report the accumulation of both proteins in abnormal endoplasmic reticulum membranous structures and the activation of the protein kinase RNA-like endoplasmic reticulum kinase pathway. Ultimately, our data bring new insight into the molecular mechanisms underlying the interplay of these two proteins, opening novel perspectives for therapeutic intervention.