相关实验视频

Updated: Jan 12, 2026

Optogenetic Phase Transition of TDP-43 in Spinal Motor Neurons of Zebrafish Larvae

Optogenetic Phase Transition of TDP-43 in Spinal Motor Neurons of Zebrafish Larvae

Published on: February 25, 2022

KCNQ2的TDP-43依赖的错误拼接会在ALS/FTD中触发内在神经元过敏性

Brian J Joseph^1,2,3, Kelly A Marshall⁴, Peter Harley⁵

¹Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.

Nature neuroscience

|November 1, 2025

概括

在ALS/FTD中,TDP-43功能障碍会导致KCNQ2错误拼接,导致非功能通道和运动神经元过度兴奋. 这可以通过反感性寡核酸来挽救,揭示了这些神经退行性疾病的关键机制.

科学领域:

神经科学是一个神经科学.
分子生物学分子生物学
遗传学是一个遗传学.

背景情况:

运动神经元过度兴奋是肌缩侧面硬化症 (ALS) 和前性痴呆症 (FTD) 的标志.
在大多数ALS和FTD病例中,TDP-43蛋白病理,包括核枯竭和细胞质聚合,是普遍存在的.
将TDP-43功能障碍与神经元过度兴奋性联系在一起的确切机制仍然不太清楚.

研究的目的:

调查TDP-43功能障碍在KCNQ2基因表达中的作用及其对ALS和FTD中运动神经元过激活性的贡献.
为了确定针对KCNQ2错误拼接的治疗策略.

主要方法:

利用诱导多能干细胞 (iPSC) 衍生的神经元和 ALS/FTD 后遗脑和脊髓组织.
在疾病模型中分析了KCNQ2mRNA拼接模式和蛋白质功能.
研究了对神经元刺激性的拼接调节性反感性寡核酸 (ASO) 的影响.

主要成果:

已证明TDP-43功能障碍诱导了KCNQ2外子的跳转,导致非功能通道 (K_v7.2).
观察到错误拼接的KCNQ2mRNA转化为非功能性蛋白质,导致ALS神经模型中的内 плазма网膜聚合和内在过激动性.
相关的KCNQ2错误拼接与更高的化TDP-43水平和患者早期疾病发病.
表明ASOs可以挽救KCNQ2错误拼接,并抑制iPSC衍生的神经元中的过度刺激性.

结论:

核TDP-43对于保持KCNQ2的表达忠实性和功能至关重要.
TDP-43功能障碍直接导致KCNQ2错误拼接,将兴奋性障碍与ALS/FTD中的TDP-43病理联系起来.
针对KCNQ2与ASO的错误拼接,代表了ALS和FTD的潜在治疗途径.

更多相关视频

Evaluation of LC3-II Release via Extracellular Vesicles in Relation to the Accumulation of Intracellular LC3-positive Vesicles

Evaluation of LC3-II Release via Extracellular Vesicles in Relation to the Accumulation of Intracellular LC3-positive Vesicles

Published on: October 18, 2024

High-throughput Yeast Plasmid Overexpression Screen

High-throughput Yeast Plasmid Overexpression Screen

Published on: July 27, 2011

相关概念视频

Alternative RNA Splicing

Alternative RNA Splicing

Alternative RNA splicing is the regulated splicing of exons and introns to produce different mature mRNAs from a single pre-mRNA. Unlike in constitutive splicing where a single gene produces a single type of mRNA, alternative splicing allows an organism to produce multiple proteins from a single gene and plays an important role in protein diversity.
There are five types of alternative RNA splicing that vary in the ways the pre-mRNA segments are removed or retained in the mature mRNA. The first...

RNA Splicing

RNA Splicing

Splicing is the process by which eukaryotic RNA is edited before its translation into protein. The RNA strand transcribed from eukaryotic DNA is called the primary transcript. The primary transcripts that become mRNAs are called precursor messenger RNAs (pre-mRNAs). Eukaryotic pre-mRNA contains alternating sequences of exons and introns. Exons are nucleotide sequences that code for proteins, whereas introns are the non-coding regions. In RNA splicing, introns are removed and exons are bonded...