一个TLK2介导的驱动细胞死亡途径将神经元退化与核包破坏联系起来
Yajie Li1,2, Huaiyuan Huang1, Jingwen Gao1
1Department of Biochemistry and Molecular Biology School of Basic Medicine, Capital Medical University, Youanmen, Beijing, 100069, China.
Nature communications
|April 10, 2025
概括
过多的会通过Tousled-like kinase 2 (TLK2) 触发神经元死亡. 抑制TLK2可以保护神经元,揭示一种称为CaToptosis的新细胞死亡途径.
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
- 细胞生物学 细胞生物学
背景情况:
- 过量的是已知的神经元细胞死亡的驱动因素.
- 诱导的神经元死亡背后的精确机制尚未完全理解.
- 托斯勒样酶 (TLK) 之前在Drosophila.中参与了这个过程.
研究的目的:
- 为了研究哺乳动物Tousled-like kinase 2 (TLK2) 在过载诱导的神经元死亡中的作用.
- 阐明TLK2对神经退行产生影响的分子机制.
- 探索TLK2作为神经退行性疾病的潜在治疗点.
主要方法:
- 在过载条件下研究了TLK2的表达,多元化和酸化.
- 利用RNA干扰和小分子抑制剂来调节TLK2活性.
- 研究了TLK2过度表达对核完整性和细胞周期标记物的影响.
- 确定了与TLK2和核外破坏相关的蛋白质复合体.
- 评估了TLK2在青光眼小鼠模型中的作用.
主要成果:
- 过载显著增加了TLK2表达,多元化和激酶活性.
- 抑制TLK2可以减少神经元死亡,以应对过载.
- 过度表达TLK2导致核外破裂,核扩大,多核和细胞循环重新进入.
- 一种TLK2,dynein轻链LC8和myosinIIA的复合体被确定为核外破坏的关键.
- 发现TLK2在小鼠绿眼瘤模型中有助于视网膜质细胞退化.
结论:
- TLK2在过载引起的神经元死亡中起着关键作用.
- TLK2通过涉及核膜破坏和细胞循环重新进入的机制调解神经退行.
- 提出了一种新的神经元死亡途径,称为CaToptosis (由诱导的Tousled-like kinase介导的细胞死亡).
- 向TLK2可能为与失调相关的神经退行性疾病提供治疗策略,例如玻璃眼.
相关概念视频
01:17The Extrinsic Apoptotic Pathway
5.5K
The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...
5.5K
01:16Necrosis
3.7K
Necrosis is considered as an “accidental” or unexpected form of cell death that ends in cell lysis. The first noticeable mention of “necrosis” was in 1859 when Rudolf Virchow used this term to describe advanced tissue breakdown in his compilation titled “Cell Pathology”.
Morphological Manifestations of Necrosis
Necrotic cells show different types of morphological appearance depending on the type of tissue and infection. In coagulative necrosis, cells become...
Morphological Manifestations of Necrosis
Necrotic cells show different types of morphological appearance depending on the type of tissue and infection. In coagulative necrosis, cells become...
3.7K
01:30Overview of Cell Death
5.6K
Cell death is an essential process where the body gets rid of old or damaged cells. Cell proliferation and death need to be balanced, as an imbalance between the two may lead to cancer or autoimmune diseases.
Cell death was observed in the early 19th century, but there was no experimental evidence to prove it. In 1842, Carl Vogt first discovered cell death in a metamorphic toad; however, it was not termed ‘cell death.’ Scientists discovered different cell death pathways only in the...
Cell death was observed in the early 19th century, but there was no experimental evidence to prove it. In 1842, Carl Vogt first discovered cell death in a metamorphic toad; however, it was not termed ‘cell death.’ Scientists discovered different cell death pathways only in the...
5.6K
01:31The Intrinsic Apoptotic Pathway
5.7K
Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
5.7K
01:03Long-term Depression
2.5K
Long-term depression, or LTD, is one of the ways by which synaptic plasticity—changes in the strength of chemical synapses—can occur in the brain. LTD is the process of synaptic weakening that occurs over time between pre and postsynaptic neuronal connections. The synaptic weakening of LTD works in opposition to synaptic strengthening by long-term potentiation (LTP) and together are the main mechanisms that underlie learning and memory.
Calcium Ion Concentration Mechanism
If over...
Calcium Ion Concentration Mechanism
If over...
2.5K
01:30Apoptosis
10.1K
Apoptosis is a combination of two Greek words, 'apo' and 'ptosis,' meaning separation and falling off, respectively. Hippocrates used this word to describe gangrene, which was caused due to bandaging of fractured bones. Apoptosis was distinguished from necrosis in 1970 when John Kerr reported observations of morphological changes occurring during apoptosis. During one experiment, he observed that the disruption of blood supply to the liver tissue resulted in a size...
10.1K