通过药理学降低炎症通路的调节来向神经炎症是蛋白质错误折叠障碍中的神经保护性
Sydney J Risen1,2, Sean W Boland1,2, Sadhana Sharma3
1Department of Environmental and Radiological Health Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado 80523, United States.
ACS chemical neuroscience
|March 20, 2024
概括
一种针对神经炎症的新疗法,通过降低NF-κB和NLRP3的调节,在普里昂病小鼠模型中保护神经元损失和认知衰退,延长寿命.
科学领域:
- 神经科学是一个神经科学.
- 免疫学 免疫学 免疫学
- 药理学 药理学是指药理学的学科.
背景情况:
- 神经炎症是蛋白质错折神经退行性疾病的关键因素,如阿尔茨海默病,帕金森病和子疾病.
- 目前对这些渐进性疾病的治疗方法有限,这凸显了对新型治疗策略的需求.
- 共享的疾病机制包括蛋白质聚合,慢性炎症和突触功能障碍,导致神经元损失和认知缺陷.
研究的目的:
- 通过降低NF-κB和NLRP3.3的调节来研究向神经炎症的神经保护潜力.
- 评估一种新的RNA向治疗尾酒 (SB_NI_112) 在子病的小鼠模型中的疗效.
主要方法:
- 利用适应小鼠的子菌株来模拟神经退行性疾病的进展.
- 通过腹腔内或鼻腔内路径给药SB_NI_112,是一种通过大脑透的,非有毒的治疗药物,向NF-κB和NLRP3.
- 在治疗和对照小鼠中评估了蛋白质聚合,质炎症,神经元损失,认知功能和寿命.
主要成果:
- SB_NI_112治疗显著地保护了行为和认知缺陷.
- 治疗减少了质细胞炎症,预防了神经元损失和海绵状变化.
- 与对照组相比,接受治疗的小鼠的寿命显著延长.
结论:
- SB_NI_112通过降低NF-κB和NLRP3的调节来显示神经保护作用,从而减缓疾病的进展.
- 这种无毒的全身疗法为治疗病和其他神经退行性疾病提供了一个有希望的原则证明.
- 需要进一步的研究来将这些发现转化为人类患者,包括对阿尔茨海默氏症和帕金森病模型的试验.
相关概念视频
03:03Amyloid Fibrils
9.5K
Amyloid fibrils are aggregates of misfolded proteins. Under most circumstances, misfolded proteins are either refolded by chaperone proteins or degraded by the proteasome. However, in the case of a mutation or a disease, these proteins can accumulate to form large clusters and often further assemble to form elongated fibers, called fibrils.
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining,...
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining,...
9.5K
01:37The Unfolded Protein Response
4.6K
The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
4.6K
01:31Regulation of the Unfolded Protein Response
2.4K
Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
2.4K
01:15Parkinson's Disease: Overview
541
Neurodegenerative disorders are progressive diseases that cause irreversible damage and loss to neurons in specific brain areas. Examples of these disorders include Parkinson's disease, Alzheimer's disease, Multiple Sclerosis (MS), and Amyotrophic Lateral Sclerosis (ALS). These disorders share characteristics such as proteinopathies, selective neuronal vulnerability, and a complex interplay between genetic and environmental factors. The primary therapeutic goal for these conditions is...
541
01:13The Proteasome
832
Eukaryotic cells can degrade proteins through several pathways. One of the most important among these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. This involves participation of a series of enzymes including— E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. This involves participation of a series of enzymes including— E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
832
01:22Alzheimer's Disease: Treatment
186
Alzheimer's Disease (AD), a neurodegenerative disorder, is pathologically identified by amyloid plaques and neurofibrillary tangles composed of tau protein. AD pharmacotherapy aims to manage cognitive symptoms, delay disease progression, and treat behavioral symptoms. The treatment is primarily symptomatic and palliative, with no definitive disease-modifying therapy available. Cholinesterase inhibitors, including donepezil (Aricept), rivastigmine (Exelon), and galantamine (Razadyne), are...
186