双功能分子靶向蛋白降解作为阿尔茨海默病及其他疾病的新治疗方式。

IF 5.6 2区 医学 Q1 CLINICAL NEUROLOGY
C Alexander Sandhof, Heide F B Murray, M Catarina Silva, Stephen J Haggarty
{"title":"双功能分子靶向蛋白降解作为阿尔茨海默病及其他疾病的新治疗方式。","authors":"C Alexander Sandhof, Heide F B Murray, M Catarina Silva, Stephen J Haggarty","doi":"10.1016/j.neurot.2024.e00499","DOIUrl":null,"url":null,"abstract":"<p><p>Alzheimer's disease (AD) is associated with memory and cognitive impairment caused by progressive degeneration of neurons. The events leading to neuronal death are associated with the accumulation of aggregating proteins in neurons and glia of the affected brain regions, in particular extracellular deposition of amyloid plaques and intracellular formation of tau neurofibrillary tangles. Moreover, the accumulation of pathological tau proteoforms in the brain concurring with disease progression is a key feature of multiple neurodegenerative diseases, called tauopathies, like frontotemporal dementia (FTD) where autosomal dominant mutations in the tau encoding MAPT gene provide clear evidence of a causal role for tau dysfunction. Observations from disease models, post-mortem histology, and clinical evidence have demonstrated that pathological tau undergoes abnormal post-translational modifications, misfolding, oligomerization, changes in solubility, mislocalization, and intercellular spreading. Despite extensive research, there are few disease-modifying or preventative therapeutics for AD and none for other tauopathies. Challenges faced in tauopathy drug development include an insufficient understanding of pathogenic mechanisms of tau proteoforms, limited specificity of agents tested, and inadequate levels of brain exposure, altogether underscoring the need for innovative therapeutic modalities. In recent years, the development of experimental therapeutic modalities, such as targeted protein degradation (TPD) strategies, has shown significant and promising potential to promote the degradation of disease-causing proteins, thereby reducing accumulation and aggregation. Here, we review all modalities of TPD that have been developed to target tau in the context of AD and FTD, as well as other approaches that with innovation could be adapted for tau-specific TPD.</p>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":" ","pages":"e00499"},"PeriodicalIF":5.6000,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Targeted protein degradation with bifunctional molecules as a novel therapeutic modality for Alzheimer's disease & beyond.\",\"authors\":\"C Alexander Sandhof, Heide F B Murray, M Catarina Silva, Stephen J Haggarty\",\"doi\":\"10.1016/j.neurot.2024.e00499\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Alzheimer's disease (AD) is associated with memory and cognitive impairment caused by progressive degeneration of neurons. The events leading to neuronal death are associated with the accumulation of aggregating proteins in neurons and glia of the affected brain regions, in particular extracellular deposition of amyloid plaques and intracellular formation of tau neurofibrillary tangles. Moreover, the accumulation of pathological tau proteoforms in the brain concurring with disease progression is a key feature of multiple neurodegenerative diseases, called tauopathies, like frontotemporal dementia (FTD) where autosomal dominant mutations in the tau encoding MAPT gene provide clear evidence of a causal role for tau dysfunction. Observations from disease models, post-mortem histology, and clinical evidence have demonstrated that pathological tau undergoes abnormal post-translational modifications, misfolding, oligomerization, changes in solubility, mislocalization, and intercellular spreading. Despite extensive research, there are few disease-modifying or preventative therapeutics for AD and none for other tauopathies. Challenges faced in tauopathy drug development include an insufficient understanding of pathogenic mechanisms of tau proteoforms, limited specificity of agents tested, and inadequate levels of brain exposure, altogether underscoring the need for innovative therapeutic modalities. In recent years, the development of experimental therapeutic modalities, such as targeted protein degradation (TPD) strategies, has shown significant and promising potential to promote the degradation of disease-causing proteins, thereby reducing accumulation and aggregation. Here, we review all modalities of TPD that have been developed to target tau in the context of AD and FTD, as well as other approaches that with innovation could be adapted for tau-specific TPD.</p>\",\"PeriodicalId\":19159,\"journal\":{\"name\":\"Neurotherapeutics\",\"volume\":\" \",\"pages\":\"e00499\"},\"PeriodicalIF\":5.6000,\"publicationDate\":\"2024-12-04\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Neurotherapeutics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.neurot.2024.e00499\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neurotherapeutics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.neurot.2024.e00499","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
引用次数: 0

摘要

阿尔茨海默病(AD)与神经元进行性变性引起的记忆和认知障碍有关。导致神经元死亡的事件与受影响脑区的神经元和神经胶质中聚集蛋白的积累有关,特别是淀粉样斑块的细胞外沉积和tau神经原纤维缠结的细胞内形成。此外,与疾病进展同时发生的病理性tau蛋白样在大脑中的积累是多种神经退行性疾病(称为tau病)的关键特征,如额颞叶痴呆(FTD),其中tau编码MAPT基因的常染色体显性突变为tau功能障碍的因果作用提供了明确的证据。来自疾病模型、死后组织学和临床证据的观察表明,病理性tau经历了异常的翻译后修饰、错误折叠、寡聚化、溶解度改变、错误定位和细胞间扩散。尽管进行了广泛的研究,但对阿尔茨海默病的疾病改善或预防性治疗方法很少,对其他牛头病变的治疗方法也很少。tau病药物开发面临的挑战包括对tau蛋白形成的致病机制了解不足,所测试药物的特异性有限,以及脑暴露水平不足,这些都强调了创新治疗方式的必要性。近年来,实验治疗模式的发展,如靶向蛋白降解(TPD)策略,已经显示出显著和有希望的潜力,促进致病蛋白的降解,从而减少积累和聚集。在这里,我们回顾了在AD和FTD背景下针对tau开发的所有TPD模式,以及其他创新的可以适用于tau特异性TPD的方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Targeted protein degradation with bifunctional molecules as a novel therapeutic modality for Alzheimer's disease & beyond.

Alzheimer's disease (AD) is associated with memory and cognitive impairment caused by progressive degeneration of neurons. The events leading to neuronal death are associated with the accumulation of aggregating proteins in neurons and glia of the affected brain regions, in particular extracellular deposition of amyloid plaques and intracellular formation of tau neurofibrillary tangles. Moreover, the accumulation of pathological tau proteoforms in the brain concurring with disease progression is a key feature of multiple neurodegenerative diseases, called tauopathies, like frontotemporal dementia (FTD) where autosomal dominant mutations in the tau encoding MAPT gene provide clear evidence of a causal role for tau dysfunction. Observations from disease models, post-mortem histology, and clinical evidence have demonstrated that pathological tau undergoes abnormal post-translational modifications, misfolding, oligomerization, changes in solubility, mislocalization, and intercellular spreading. Despite extensive research, there are few disease-modifying or preventative therapeutics for AD and none for other tauopathies. Challenges faced in tauopathy drug development include an insufficient understanding of pathogenic mechanisms of tau proteoforms, limited specificity of agents tested, and inadequate levels of brain exposure, altogether underscoring the need for innovative therapeutic modalities. In recent years, the development of experimental therapeutic modalities, such as targeted protein degradation (TPD) strategies, has shown significant and promising potential to promote the degradation of disease-causing proteins, thereby reducing accumulation and aggregation. Here, we review all modalities of TPD that have been developed to target tau in the context of AD and FTD, as well as other approaches that with innovation could be adapted for tau-specific TPD.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Neurotherapeutics
Neurotherapeutics 医学-神经科学
CiteScore
11.00
自引率
3.50%
发文量
154
审稿时长
6-12 weeks
期刊介绍: Neurotherapeutics® is the journal of the American Society for Experimental Neurotherapeutics (ASENT). Each issue provides critical reviews of an important topic relating to the treatment of neurological disorders written by international authorities. The Journal also publishes original research articles in translational neuroscience including descriptions of cutting edge therapies that cross disciplinary lines and represent important contributions to neurotherapeutics for medical practitioners and other researchers in the field. Neurotherapeutics ® delivers a multidisciplinary perspective on the frontiers of translational neuroscience, provides perspectives on current research and practice, and covers social and ethical as well as scientific issues.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信