来自神经元的大囊泡挤出可能有助于传播致病蛋白聚集体并促进炎症反应。导致神经退行性疾病的两种机制。调节大囊泡挤出的因素,如蛋白质应激的C.elegans接触神经元产生的外基因,知之甚少。这里,我们记录了机械力可以显着增强蛋白质应激神经元的exopher挤出。来自C.elegansALMR神经元的Exopher产生在成年第2天或第3天达到峰值,与C.elegans生殖峰值一致。秀丽隐杆线虫种系的遗传破坏,精子,卵母细胞,或卵/早期胚胎的产生可以在高峰期间强烈抑制从ALMR神经元的外泌体挤出。相反,通过与雄性交配或通过阻止产卵的遗传干预来诱导卵保留,可以在生殖后期恢复卵的产量,可以大大增加ALMRexopher的产量。总的来说,促进ALMRexopher产生的基因干预与子宫长度扩大相关,抑制ALMRexopher产生的基因干预与子宫长度缩短相关.除了受精卵的影响,通过用卵母细胞填充子宫可以增强ALMRexopher的产生,死蛋,甚至是流体,支持扩张的后果,而不是受精卵的存在,构成了外在诱导刺激。我们得出的结论是,子宫占领的机械力增强了近端蛋白应激母体神经元的外向挤压。我们的观察使人们注意到机械信号在细胞外囊泡产生和聚集体传播机制中的潜在重要性。在神经退行性疾病中加强对机械生物学的关注。
神经元是大脑和神经系统中的特化细胞,在大脑和身体其他部分之间传递信号,使人类和动物能够对内部和外部刺激做出反应。为了使该通信系统有效运行,神经元必须保持健康。神经元以各种方式维持其功能,包括通过去除可能损害神经元功能的过量或受损的细胞成分(如细胞器和蛋白质聚集体)。一种方法是挤压细胞器和聚集体。在“挤压事件”期间,要去除的物质聚集在质膜的出芽部分,形成从神经元排出物质的囊泡。然而,驱动挤压过程的因素仍然未知。为了调查,Wang,Guasp,Salametal.在秀丽隐杆线虫中进行的蛔虫实验,发现某种类型的神经元中的挤压事件的数量在繁殖高峰时增加。更具体地说,更多的挤压事件与受精卵的存在有关,它们在被放置之前在子宫中积聚。破坏鸡蛋,精子或受精过程抑制了挤压事件的增加,表明受精卵的存在是原因。为了确定鸡蛋如何触发挤压事件,Wang等人。用死卵拉伸子宫,未受精卵或通过注射液体,发现这些方法中的每一种都增加了挤出事件的数量。进一步的分析表明,子宫的这种机械拉伸向神经元发出信号,表明繁殖已经开始,鼓励神经元去除旧的成分并优化它们的功能。Wang等人。假设这种伸展反应可以支持有助于成功繁殖的神经元行为,例如感知食物和选择产卵的地方。这些发现增加了我们对活生物体中触发囊泡挤出的因素的理解。这些观察结果可能对人类神经退行性疾病如阿尔茨海默病产生影响,蛋白质聚集在神经元中。与阿尔茨海默病相关的因素产生的机械信号,比如高血压,可能会影响神经元的挤压,并有助于神经退行性疾病中聚集体转移的某些机制。
Large vesicle extrusion from neurons may contribute to spreading pathogenic protein aggregates and promoting inflammatory responses, two mechanisms leading to neurodegenerative disease. Factors that regulate the extrusion of large vesicles, such as exophers produced by proteostressed C. elegans touch neurons, are poorly understood. Here, we document that mechanical force can significantly potentiate exopher extrusion from proteostressed neurons. Exopher production from the C. elegans ALMR neuron peaks at adult day 2 or 3, coinciding with the C. elegans reproductive peak. Genetic disruption of C. elegans germline, sperm, oocytes, or egg/early embryo production can strongly suppress exopher extrusion from the ALMR neurons during the peak period. Conversely, restoring egg production at the late reproductive phase through mating with males or inducing egg retention via genetic interventions that block egg-laying can strongly increase ALMR exopher production. Overall, genetic interventions that promote ALMR exopher production are associated with expanded uterus lengths and genetic interventions that suppress ALMR exopher production are associated with shorter uterus lengths. In addition to the impact of fertilized eggs, ALMR exopher production can be enhanced by filling the uterus with oocytes, dead eggs, or even fluid, supporting that distention consequences, rather than the presence of fertilized eggs, constitute the exopher-inducing stimulus. We conclude that the mechanical force of uterine occupation potentiates exopher extrusion from proximal proteostressed maternal neurons. Our observations draw attention to the potential importance of mechanical signaling in extracellular vesicle production and in aggregate spreading mechanisms, making a case for enhanced attention to mechanobiology in neurodegenerative disease.
Neurons are specialized cells in the brain and nervous system that transmit signals between the brain and the rest of the body, enabling humans and animals to react to internal and external stimuli. For this communication system to function effectively, neurons must remain healthy. Neurons maintain their function in a variety of ways, including by removing excess or damaged cellular components (such as organelles and protein aggregates) that could compromise neuron function. One way to do this is by extruding organelles and aggregates. During ‘extrusion events’, the material to be removed is gathered within a budding portion of the plasma membrane, which forms a vesicle that ejects the material from the neuron. However, the factors driving the extrusion process remained unknown. To investigate, Wang, Guasp, Salam et al. conducted experiments in the roundworm Caenorhabditis elegans, finding that the number of extrusion events in a certain type of neuron increases at the peak of reproduction. More specifically, a greater number of extrusion events were associated with the presence of fertilized eggs, which accumulate in the uterus before they are laid. Disrupting eggs, sperm or the fertilization process suppressed the increase in extrusion events, suggesting the presence of fertilized eggs is responsible. To determine how the eggs might trigger extrusion events, Wang et al. stretched the uterus using dead eggs, unfertilized eggs or by injecting fluid, finding that each of these approaches increased the number of extrusion events. Further analysis suggests that this mechanical stretching of the uterus signals to the neurons that reproduction has started, encouraging the neurons to remove old components and optimize their function. Wang et al. hypothesize that this stretch response could support neuronal behaviors that aid in successful reproduction, such as sensing food and selecting where to lay eggs. The findings increase our understanding of the factors that trigger vesicle extrusion in living organisms. These observations could have implications for human neurodegenerative diseases such as Alzheimer’s disease, in which protein aggregates accumulate in neurons. It is possible that mechanical signals generated by factors associated with Alzheimer’s disease, such as high blood pressure, could influence neuronal extrusion and contribute to some of the mechanisms underlying aggregate transfer in neurodegenerative diseases.