甲状腺激素载体Mct8/Oatp1c1缺乏的小鼠的蛋白质组分析揭示了参与运动功能的新型失调的点分子
Devon Siemes1, Pieter Vancamp2, Boyka Markova2
1Department of Immunodynamics, Institute for Experimental Immunology and Imaging, University Duisburg-Essen, 45141 Essen, Germany.
Cells
|October 27, 2023
概括
甲状腺激素 (TH) 载体MCT8缺乏会损害神经功能,导致严重的运动残疾. 这项研究确定了大脑中减少的Pde10a表达是MCT8缺乏的潜在关键途径.
科学领域:
- 神经内分泌学神经内分泌学
- 分子神经科学 分子神经科学
- 遗传学 是一个遗传学.
背景情况:
- 由于甲状腺激素 (TH) 在大脑中的作用不足,MCT8载体缺乏导致严重的神经发育和运动障碍.
- Mct8/Oatp1c1双淘汰赛 (DKO) 小鼠作为模型,显示中心TH缺乏和运动缺陷,反映人类MCT8缺乏.
- 驱动这些神经运动症状的精确分子通路仍然不太清楚.
研究的目的:
- 调查Mct8/Oatp1c1 DKO小鼠大脑中的蛋白质变化,以确定导致神经运动缺陷的分子途径.
- 将蛋白质组发现与现有的RNA测序数据进行比较,以验证分子变化.
- 为了确定参与MCT8缺乏症的发病过程中的新型分子候选者.
主要方法:
- 使用液态染色体质谱的蛋白质组分析,对21天大的野生型 (WT) 和DKO小鼠的皮质和条状大脑部分进行分析.
- 对2900多种已识别的蛋白质进行量化和统计分析,以发现基因型特异性差异.
- 将蛋白质组数据与已发布的RNA测序数据集集集成,以评估转录组和蛋白质组相关性.
主要成果:
- 在WT和DKO小鼠之间检测到67种蛋白质表达的显著差异.
- 蛋白质组的变化与先前公布的RNA测序数据有显著的重叠.
- DKO小鼠表现出髓相关蛋白和已知的TH调节的神经元点的减少表达.
- 在DKO小鼠中发现并证实了Pde10a的蛋白质和mRNA表达减少,Pde10a是多巴胺信号传递中的条状酶.
结论:
- 在DKO小鼠的条形体中减少Pde10a表达是MCT8缺乏的一个新发现.
- 改变的PDE10A活性与 dystonia 有关,这表明减少基底的PDE10A表达可能是人类MCT8缺乏症的关键致病机制.
- 这些发现为MCT8缺乏症中神经运动症状的分子基础提供了新的见解,强调了Pde10a作为潜在的治疗点.
相关概念视频
01:44The Significance of Membrane Transport
27.4K
The transport of solutes across the cell membrane is essential for metabolic processes, like maintaining cell size and volume, generating the action potential, exchanging nutrients and gases, etc. Membrane transport can be either passive or active. It can be simple diffusion, facilitated, or mediated transport aided by transport proteins such as transporters and channels.
Transporters facilitate either an active or passive movement of solutes. They can allow a single-molecule transport down its...
Transporters facilitate either an active or passive movement of solutes. They can allow a single-molecule transport down its...
27.4K
01:06Carrier-Mediated Transport
448
Carrier-mediated transport is a pivotal process in drug absorption, particularly for lipid-insoluble drugs, and encompasses facilitated diffusion and active transport. Facilitated diffusion allows drugs to move along their concentration gradient without energy expenditure, while active transport utilizes ATP to drive drug movement against this gradient.
Active transport involves two types of membrane-spanning transporters: uptake and efflux. Uptake transporters are expressed in the small...
Active transport involves two types of membrane-spanning transporters: uptake and efflux. Uptake transporters are expressed in the small...
448
01:20Synthesis and Regulation of Thyroid Hormones
4.7K
Low blood levels of the thyroid hormones — triiodothyronine (T3) and thyroxine (T4) — signal the hypothalamus to release the thyrotropin-releasing hormone (TRH). TRH then reaches the pituitary gland and stimulates the release of thyroid-stimulating hormone(TSH) into the bloodstream.
Upon reaching the thyroid gland, TSH stimulates the follicular cells' active uptake of iodide ions from the blood. The ions diffuse to the apical surface of the cells and are oxidized to iodine. The...
Upon reaching the thyroid gland, TSH stimulates the follicular cells' active uptake of iodide ions from the blood. The ions diffuse to the apical surface of the cells and are oxidized to iodine. The...
4.7K
01:18Functions of Thyroid Hormones
2.8K
The thyroid hormone (TH) plays a pivotal role in the intricate orchestration of physiological processes, exerting profound effects on development, metabolism, and homeostasis throughout different life stages.
TH is indispensable for the normal development and maturation of the skeletal, muscular, and nervous systems during fetal and childhood growth. It facilitates bone mineral turnover and regulates protein synthesis in developing tissues, contributing significantly to overall growth and...
TH is indispensable for the normal development and maturation of the skeletal, muscular, and nervous systems during fetal and childhood growth. It facilitates bone mineral turnover and regulates protein synthesis in developing tissues, contributing significantly to overall growth and...
2.8K