Department of Geriatric Medicine, Tokyo Medical University, Shinjuku-ku, Japan.
Cerebellum. 2010 Jun;9(2):183-9. doi: 10.1007/s12311-010-0158-9.
This mini-review focuses on the possible relevance of 14-3-3 proteins in spinocerebellar ataxia type 1 (SCA1). 14-3-3 proteins are mainly localized in the synapses and neuronal cytoplasm, and seven isoforms have been identified in mammals. This family of proteins was initially identified as adaptor proteins which bind to phosphoserine-containing motifs. Binding motifs and potential functions of 14-3-3 proteins are now recognized to have a wide range of functional relevance. SCA1 is an autosomal-dominant neurodegenerative disorder and is linked to polyglutamine expansion (ataxin-1 protein). The Zoghbi and Orr group showed direct interaction of 14-3-3 proteins with ataxin-1 where nuclear recruitment of the ataxin-1 protein is dependent on its phosphorylation. This targeted binding of 14-3-3 protein to phosphorylated ataxin-1 to stabilize ataxin-1 in cellular models was corroborated by our double-labeling study for expanded polyglutamine and 14-3-3 proteins which demonstrated colocalization of these two epitopes in the neuronal nuclei in human autopsied brains with SCA1. Ataxin-1/14-3-3 protein interaction is a new potential target for therapeutic intervention in the treatment of SCA1.
本篇综述主要聚焦于 14-3-3 蛋白在脊髓小脑共济失调 1 型（SCA1）中的潜在相关性。14-3-3 蛋白主要定位于突触和神经元细胞质中，在哺乳动物中已鉴定出七种同工型。该蛋白家族最初被鉴定为与磷酸丝氨酸基序结合的衔接蛋白。现在已经认识到，14-3-3 蛋白的结合基序和潜在功能具有广泛的功能相关性。SCA1 是一种常染色体显性神经退行性疾病，与多聚谷氨酰胺扩展（ataxin-1 蛋白）有关。Zoghbi 和 Orr 小组表明 14-3-3 蛋白与 ataxin-1 之间存在直接相互作用，ataxin-1 蛋白的核募集依赖于其磷酸化。我们的双重标记研究证实了 14-3-3 蛋白对磷酸化 ataxin-1 的靶向结合可稳定细胞模型中的 ataxin-1，该研究表明在具有 SCA1 的人类尸检大脑的神经元核中，这两个表位存在共定位。Ataxin-1/14-3-3 蛋白相互作用是治疗 SCA1 的一种新的潜在治疗靶点。
