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棘蛋白 2 和 Igsf9b 协调调节轴突起始段的细胞结构。

Prickle2 and Igsf9b Coordinately Regulate the Cytoarchitecture of the Axon Initial Segment.

机构信息

Department of Cell Pharmacology, Nagoya University.

Department of Biochemistry, Yamanashi University.

出版信息

Cell Struct Funct. 2020 Sep 1;45(2):143-154. doi: 10.1247/csf.20028. Epub 2020 Jul 8.

DOI:10.1247/csf.20028
PMID:32641624
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10511046/
Abstract

Prickle2 has been identified in genetic studies of subjects with autism spectrum disorder (ASD) and epilepsy, but the pathological mechanism of Prickle2 remains to be fully understood. Proteomic analysis of Prickle2 with mass spectrometry revealed twenty-eight Prickle2 interactors, including immunoglobulin superfamily member 9b (Igsf9b), in the brain. Here, because Igsf9 family proteins are associated with psychiatric diseases and seizures, we studied the physiological interaction between Prickle2 and Igsf9b. Prickle2 colocalized with Igsf9b in cultured hippocampal neurons. Knockdown of Prickle2 affected the subcellular localization of Igsf9b. Interestingly, Igsf9b localized along axonal processes in a pattern opposite to the ASD-related molecule ANK3/AnkG. AnkG is a major component of the axon initial segment (AIS), where a variety of ASD and epilepsy susceptibility proteins accumulate. Igsf9b-knockdown neurons displayed altered AnkG localization. Prickle2 depletion caused defects in AnkG and voltage-gated Na+ channel localization, resulting in altered network activity. These results support the idea that Prickle2 regulates AnkG distribution by controlling the proper localization of Igsf9b. The novel function of Prickle2 in AIS cytoarchitecture provides new insights into the shared pathology of ASD and epilepsy.Key words: Prickle2, Igsf9b, axon initial segment, neuronal excitability, ASD.

摘要

棘蛋白 2（Prickle2）在自闭症谱系障碍（ASD）和癫痫患者的遗传研究中被鉴定出来，但 Prickle2 的病理机制仍有待充分理解。利用质谱对 Prickle2 的蛋白质组学分析揭示了大脑中有 28 种 Prickle2 相互作用蛋白，包括免疫球蛋白超家族成员 9b（Igsf9b）。由于 Igsf9 家族蛋白与精神疾病和癫痫有关，因此我们研究了 Prickle2 和 Igsf9b 之间的生理相互作用。Prickle2 在培养的海马神经元中与 Igsf9b 共定位。敲低 Prickle2 会影响 Igsf9b 的亚细胞定位。有趣的是，Igsf9b 沿轴突突沿着与 ASD 相关分子 ANK3/AnkG 相反的模式定位。AnkG 是轴突起始段（AIS）的主要成分，多种 ASD 和癫痫易感性蛋白在此积累。Igsf9b 敲低神经元显示出 AnkG 定位的改变。Prickle2 耗竭导致 AnkG 和电压门控 Na+通道定位缺陷，从而导致网络活动改变。这些结果支持 Prickle2 通过控制 Igsf9b 的适当定位来调节 AnkG 分布的观点。Prickle2 在 AIS 细胞结构中的新功能为 ASD 和癫痫的共同病理提供了新的见解。

关键词

棘蛋白 2（Prickle2）、免疫球蛋白超家族成员 9b（Igsf9b）、轴突起始段（AIS）、神经元兴奋性、ASD。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b4b/10511046/7baf2e2f60c0/csf_45_20028-f007.jpg
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