人类大脑中神经元肌动蛋白细胞骨架功能获得

Neuronal actin cytoskeleton gain of function in the human brain.

机构信息

State University of New York at Buffalo, 875 Ellicott St., Buffalo, NY, 14203, USA.

出版信息

EBioMedicine. 2023 Sep;95:104725. doi: 10.1016/j.ebiom.2023.104725. Epub 2023 Jul 28.

DOI:10.1016/j.ebiom.2023.104725

PMID:37517100

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10404607/

Abstract

BACKGROUND

While advancements in imaging techniques have led to major strides in deciphering the human brain, successful interventions are elusive and represent some of the most persistent translational gaps in medicine. Human restricted CHRFAM7A has been associated with neuropsychiatric disorders.

METHODS

The physiological role of CHRFAM7A in human brain is explored using multiomics approach on 600 post mortem human brain tissue samples. The emerging pathways and mechanistic hypotheses are tested and validated in an isogenic hiPSC model of CHRFAM7A knock-in medial ganglionic eminence progenitors and neurons.

FINDINGS

CHRFAM7A is identified as a modulator of intracellular calcium dynamics and an upstream regulator of Rac1. Rac1 activation re-designs the actin cytoskeleton leading to dynamic actin driven remodeling of membrane protrusion and a switch from filopodia to lamellipodia. The reinforced cytoskeleton leads to an advantage to tolerate stiffer mechanical properties of the extracellular environment.

INTERPRETATION

CHRFAM7A modifies the actin cytoskeleton to a more dynamic and stiffness resistant state in an α7nAChR dependent manner. CHRFAM7A may facilitate neuronal adaptation to changes in the brain environment in physiological and pathological conditions contributing to risk or recovery. Understanding how CHRFAM7A affects human brain requires human studies in the areas of memory formation and erasure, cognitive reserve, and neuronal plasticity.

FUNDING

This work is supported in part by the Community Foundation for Greater Buffalo (Kinga Szigeti). Also, in part by the International Society for Neurochemistry (ISN) and The Company of Biologists (Nicolas Rosas). ROSMAP is supported by NIA grants P30AG10161, P30AG72975, R01AG15819, R01AG17917. U01AG46152, and U01AG61356.

摘要

背景

尽管成像技术的进步使得人类大脑的破译取得了重大进展，但成功的干预措施仍难以实现，这代表了医学领域中一些最持久的转化差距。人类受限 CHRFAM7A 与神经精神疾病有关。

方法

使用多组学方法在 600 个人死后脑组织样本上探索 CHRFAM7A 在人类大脑中的生理作用。在 CHRFAM7A 基因敲入中脑神经节隆起祖细胞和神经元的同基因 hiPSC 模型中测试和验证新出现的途径和机制假设。

结果

CHRFAM7A 被鉴定为细胞内钙动力学的调节剂和 Rac1 的上游调节剂。Rac1 的激活重新设计了肌动蛋白细胞骨架，导致膜突起的动态肌动蛋白驱动重塑，并从丝状伪足转换为片状伪足。强化的细胞骨架导致能够耐受细胞外环境更硬的机械特性。

解释

CHRFAM7A 以依赖于α7nAChR 的方式将肌动蛋白细胞骨架修饰为更具动态性和抗刚性的状态。CHRFAM7A 可能有助于神经元适应生理和病理条件下大脑环境的变化，从而增加患病或康复的风险。了解 CHRFAM7A 如何影响人类大脑需要在记忆形成和消除、认知储备和神经元可塑性等领域进行人类研究。

资助

这项工作部分得到大布法罗社区基金会（Kinga Szigeti）的支持。部分由国际神经化学学会（ISN）和 The Company of Biologists（Nicolas Rosas）支持。ROSMAP 由 NIA 拨款 P30AG10161、P30AG72975、R01AG15819、R01AG17917、U01AG46152 和 U01AG61356 支持。