TBCK-缺乏导致病患衍生神经元中的分区特异性mRNA和 lysosomal trafficking缺陷
Marco Flores-Mendez1,2, Jesus A Tintos-Hernández1,2, Leonardo Ramos-Rodriguez3
1Department of Pediatrics, Division of Neurology, The Children's of Philadelphia, Philadelphia, PA.
bioRxiv : the preprint server for biology
|March 17, 2025
概括
损失TBCK蛋白质会通过破坏mRNA和神经元中的溶酶体运输而导致神经退行. 这项研究揭示了TBCKK.
科学领域:
- 神经科学是一个神经科学.
- 遗传学 遗传学 是一个
- 细胞生物学 细胞生物学
背景情况:
- 单一的儿科神经退行性疾病提供了对神经元脆弱性的见解.
- TBCK-脑神经病变 (TBCKE) 是一种罕见的自体衰退性疾病,与TBCK基因变异有关,导致神经发育延迟和运动神经元疾病.
- 目前尚不完全了解TBCK蛋白的精确功能.
研究的目的:
- 研究TBCK蛋白在人类神经元中的生理作用.
- 为了阐明TBCK-脑神经病变背后的细胞机制.
- 为了确定TBCK的分子相互作用和细胞功能.
主要方法:
- 使用患者衍生的iPSCs生成人类神经元TBCKE模型.
- 进行了公正的蛋白质组分析,以确定TBCK的相互作用伙伴.
- 使用免疫光显微镜来评估蛋白质局部化和与mRNA的同位化.
- 在轴突和体内部分的量化mRNA水平.
- 在TBCK缺乏的神经元中评估了溶酶体贩运和JIP4蛋白水平.
主要成果:
- 确定TBCK是FERRY mRNA运输复合体的一部分,与PPP1R21,C12orf4和Cryzl1.1相互作用.
- 证明TBCK损失会降低C12ORF4蛋白水平,这表明它有调节作用.
- 显示的TBCK局部化到内溶性体囊泡,并与溶性体中的mRNA一起局部化.
- 揭示了TBCK缺陷神经元中的轴突mRNA含量和JIP4蛋白水平的降低.
- 在TBCK缺乏的神经元中观察到显著的溶酶体轴突逆行性贩运缺陷.
结论:
- TBCK调解mRNA的内溶酶体贩运,特别是在神经元轴突区内通过溶酶体.
- 由于TBCK缺乏,mRNA和 lysosomal trafficking中的分区特异性缺陷产生.
- 这些贩运缺陷与在TBCKE中观察到的选择性神经元脆弱性有关.
更多相关视频
10:38Author Spotlight: Understanding the Impact of Pathological Proteins on Axonal Transport in Neurodegenerative Diseases
Published on: December 22, 2023
396
13:46An Improved Protocol to Purify and Directly Mono-Biotinylate Recombinant BDNF in a Tube for Cellular Trafficking Studies in Neurons
Published on: July 11, 2020
5.7K
相关概念视频
01:31Translation
141.2K
Lesson: Translation
Translation is the process of synthesizing proteins from the genetic information carried by messenger RNA (mRNA). Following transcription, it constitutes the final step in the expression of genes. This process is carried out by ribosomes, complexes of protein and specialized RNA molecules. Ribosomes, transfer RNA (tRNA), and other proteins produce a chain of amino acids—the polypeptide—as the end product of translation.
Translation Produces the Building Blocks of...
Translation is the process of synthesizing proteins from the genetic information carried by messenger RNA (mRNA). Following transcription, it constitutes the final step in the expression of genes. This process is carried out by ribosomes, complexes of protein and specialized RNA molecules. Ribosomes, transfer RNA (tRNA), and other proteins produce a chain of amino acids—the polypeptide—as the end product of translation.
Translation Produces the Building Blocks of...
141.2K
01:22Lysosomal Hydrolases
3.7K
Lysosomes are the site for the degradation of macromolecules and biological polymers released during membrane trafficking events such as secretory, endocytic, autophagic, and phagocytic pathways. The membrane-enclosed area of the lysosome, called the lumen, contains hydrolytic enzymes active in an acidic environment. These acid hydrolases are functional at a pH between 4.5 and 5 and are involved in cellular processes such as cell signaling, energy metabolism, restoration of the plasma membrane,...
3.7K
01:00Enzyme-linked Receptors
76.8K
Enzyme-linked receptors are proteins that act as both receptor and enzyme, activating multiple intracellular signals. This is a large group of receptors that include the receptor tyrosine kinase (RTK) family. Many growth factors and hormones bind to and activate the RTKs.
Neurotrophin (NT) receptors are a family of RTKs, including trkA, trkB, and trkC (tropomyosin-related kinase) receptors. TrkA is specific for nerve growth factor (NGF), neurotrophin-6, and neurotrophin-7. TrkB binds...
Neurotrophin (NT) receptors are a family of RTKs, including trkA, trkB, and trkC (tropomyosin-related kinase) receptors. TrkA is specific for nerve growth factor (NGF), neurotrophin-6, and neurotrophin-7. TrkB binds...
76.8K
01:15Receptor Downregulation in MVBs
2.0K
Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR...
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR...
2.0K