LRRK2 G2019S Mutation Induces Dendrite Degeneration through Mislocalization and Phosphorylation of Tau by Recruiting Autoactivated GSK3β
LRRK2 G2019S Mutation Induces Dendrite Degeneration through Mislocalization and Phosphorylation of Tau by Recruiting Autoactivated GSK3β
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DOI：
10.1523/jneurosci.1737-10.2010
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发表时间：
2010-09-29
影响因子：
5.3
通讯作者：
Chien, Cheng-Ting
中科院分区：
文献类型：
--
作者：
Lin, Chin-Hsien;Tsai, Pei-I;Chien, Cheng-Ting
神经元内tau聚集是富含亮氨酸重复激酶2 （LRRK2）常染色体显性突变的帕金森病（PD）的独特病理特征。最常见的LRRK2突变G2019S（氨基酸上甘氨酸到丝氨酸的替代2019）通过不明确的发病机制导致神经突萎缩。我们发现G2019S突变体在果蝇树突树突神经元中的表达诱导了树突轴突蛋白tau的错定位，导致树突变性。g2019s诱导的树突变性通过降低tau蛋白水平而受到抑制，并通过tau共表达而加重。另外的遗传分析表明，G2019S和tau协同作用，导致微管断裂、包涵体形成和枝晶变性。在机制上，过度激活的G2019S通过果蝇糖原合成酶激酶3 β同源物Shaggy （Sgg）促进T212位点的tau磷酸化。G2019S增加了自身活化的Sgg的募集，从而诱导tau蛋白的过度磷酸化和错定位，导致树突变性。
Intraneuronal tau aggregations are distinctive pathological features of Parkinson's disease (PD) with autosomal-dominant mutations in leucine-rich repeat kinase 2 (LRRK2). The most prevalent LRRK2 mutation, G2019S (glycine to serine substitution at amino acid 2019), causes neurite shrinkage through unclear pathogenetic mechanisms. We found that expression of G2019S mutant in Drosophila dendritic arborization neurons induces mislocalization of the axonal protein tau in dendrites and causes dendrite degeneration. G2019S-induced dendrite degeneration is suppressed by reducing the level of tau protein and aggravated by tau coexpression. Additional genetic analyses suggest that G2019S and tau function synergistically to cause microtubule fragmentation, inclusion formation, and dendrite degeneration. Mechanistically, hyperactivated G2019S promotes tau phosphorylation at the T212 site by the Drosophila glycogen synthase kinase 3 beta homolog Shaggy (Sgg). G2019S increases the recruitment of autoactivated Sgg, thus inducing hyperphosphorylation and mislocalization of tau with resultant dendrite degeneration.