通过AMPK介导的自道激活促进了ΔFosB降解,以改善勒沃多巴诱导的运动障碍
Ke Liu1, Zhaoyuan Zhang1, Yu Xu1
1Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Cellular signalling
|March 3, 2024
概括
甲胺治疗激活AMP激活蛋白激酶 (AMPK) 介导的自途径,促进ΔFosB的降解,并减少帕金森病模型中的勒沃多巴诱导失动症 (LID).
科学领域:
- 神经科学是一个神经科学.
- 细胞生物学 细胞生物学
- 药理学 药理学是指药理学的学科.
背景情况:
- 服用莱沃多巴的帕金森病 (PD) 患者会出现运动并发症,如莱沃多巴诱导的运动障碍症 (LID).
- 精确的LID病原机制仍然不清楚,新出现的证据表明自功能障碍.
- LID显著损害了PD患者的生活质量.
研究的目的:
- 调查AMP激活蛋白激酶 (AMPK) 介导的自途径在LID中的作用.
- 通过这种途径探索甲福尔明在缓解LID方面的治疗潜力.
主要方法:
- 通过使用6-氧多巴胺 (6-OHDA) 和慢性列沃多巴治疗,建立了LID的老鼠模型.
- 甲福明,AICAR,化合物C和对LID症状和分子标记物的影响被评估为体内和体外.
- 分析了AMPK通路活性,自性标记物和FosB-ΔFosB水平,使用西方抹杀,RT-qPCR,免疫光和传输电子显微镜.
主要成果:
- 慢性列沃多巴治疗损害了AMPK酸化和自酶-溶酶融合,导致PD大鼠的FosB-ΔFosB积累.
- 甲胺干预改善了LID症状,减少了异常的大脑振荡,并促进了AMPK酸化和自.
- 甲胺促进了FosB-ΔFosB降解,AMPK和自抑制剂可以逆转这种效应.
结论:
- 长期的甲福明治疗通过激活AMPK介导的自途径并促进ΔFosB降解来减轻LID的发展.
- 由AMPK介导的自途径代表了LID.的新治疗标.
- 甲胺显示作为治疗候选人的承诺在帕金森病中管理勒沃多巴诱导的运动障碍.
相关概念视频
01:24Parkinson's Disease: Treatment
268
Neurodegenerative disorders, such as Parkinson's Disease (PD), involve the gradual and irreversible destruction of neurons in particular brain areas. These disorders exhibit standard features like proteinopathies, selective vulnerability of some neurons, and an interaction of intrinsic properties, genetics, and environmental influences in neural injury.
Parkinson's Disease is primarily a result of the loss of dopaminergic neurons in the substantia nigra pars compacta. The cornerstone of...
Parkinson's Disease is primarily a result of the loss of dopaminergic neurons in the substantia nigra pars compacta. The cornerstone of...
268
01:27Autophagy
4.2K
Autophagy is a self-digesting process by which a cell protects itself from threats both within and outside the cell, ranging from abnormal proteins to invading bacteria. In this process, obsolete components of the cell and invading microbes are degraded by hydrolytic enzymes active in an acidic environment of the lysosomal lumen.
An autophagic pathway consists of a series of signaling events activated in response to diverse stress and physiological conditions such as food deprivation,...
An autophagic pathway consists of a series of signaling events activated in response to diverse stress and physiological conditions such as food deprivation,...
4.2K
01:22Lysosomal Hydrolases
3.8K
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,...
3.8K
01:18Autophagic Cell Death
3.4K
Christian de Duve discovered “autophagy,” a process in which cellular components are engulfed by membrane-bound organelles called autophagosomes. The autophagosomes then fuse with lysosomes to digest the enclosed contents. Autophagy is generally activated in cells to prevent cell death. However, cell death is triggered when the damage is beyond repair.
Autophagy and Apoptosis
Autophagy can activate apoptosis. In normal conditions, the autophagy activating protein Beclin-1 and...
Autophagy and Apoptosis
Autophagy can activate apoptosis. In normal conditions, the autophagy activating protein Beclin-1 and...
3.4K
01:22PI3K/mTOR/AKT Signaling Pathway
3.6K
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast, mTORC2 consists of a...
3.6K
01:36Delivery Pathways to the Lysosome
6.5K
Eukaryotic cells use different mechanisms to eliminate toxic waste obsolete and worn-out substances. Lysosomes play a pivotal role in this, and hence, these substances are carried to the lysosome from other parts of the cell and extracellular space through different pathways. The most elaborately studied pathways to the lysosome are the endocytic pathways.
Endocytosis
In endocytosis, the cell membrane takes up macromolecules and particles from the surrounding medium. Clathrin-mediated...
Endocytosis
In endocytosis, the cell membrane takes up macromolecules and particles from the surrounding medium. Clathrin-mediated...
6.5K