Targeting the Unfolded Protein Response as a Disease-Modifying Pathway in Dementia.
Targeting the Unfolded Protein Response as a Disease-Modifying Pathway in Dementia.
复制标题
DOI：
10.3390/ijms23042021
复制
发表时间：
2022-02-11
影响因子：
5.6
通讯作者：
Underwood BR
中科院分区：
文献类型：
--
作者：
Sidhom E;O'Brien JT;Butcher AJ;Smith HL;Mallucci GR;Underwood BR
痴呆症是一项全球性的医学和社会挑战；它具有毁灭性的个人、社会和经济代价，随着世界人口老龄化，这些代价将迅速增加。尽管如此，目前还没有治疗痴呆症的疾病修正疗法；目前的疗法只是适度地改善了症状，但并不能改变结果。因此，迫切需要新的治疗方法--特别是任何可以减缓疾病进展的方法。许多导致痴呆的神经退行性疾病的特点是对异常蛋白质生产和脑细胞错误折叠的常见病理反应，这增加了针对这些共同过程的疗法的广泛应用的可能性。未折叠蛋白反应(UPR)就是这样一种机制。UPR是对蛋白质折叠异常的高度保守的细胞应激反应，广泛存在于神经退行性疾病中。在这篇综述中，我们描述了UPR的基本机制，以及它在痴呆中过度激活和致病的证据，以及在这些疾病的小鼠模型中其治疗手法具有显著的神经保护作用。我们讨论了被确定为潜在的UPR修饰治疗剂的药物--特别是获得许可的抗抑郁药曲唑酮--并回顾了它们在人类人群中使用的流行病学和试验数据。最后，我们探索了未来研究使用曲唑酮或类似的UPR调节化合物用于痴呆症患者疾病修改的潜在益处的方向。
Dementia is a global medical and societal challenge; it has devastating personal, social and economic costs, which will increase rapidly as the world’s population ages. Despite this, there are no disease-modifying treatments for dementia; current therapy modestly improves symptoms but does not change the outcome. Therefore, new treatments are urgently needed—particularly any that can slow down the disease’s progression. Many of the neurodegenerative diseases that lead to dementia are characterised by common pathological responses to abnormal protein production and misfolding in brain cells, raising the possibility of the broad application of therapeutics that target these common processes. The unfolded protein response (UPR) is one such mechanism. The UPR is a highly conserved cellular stress response to abnormal protein folding and is widely dysregulated in neurodegenerative diseases. In this review, we describe the basic machinery of the UPR, as well as the evidence for its overactivation and pathogenicity in dementia, and for the marked neuroprotective effects of its therapeutic manipulation in murine models of these disorders. We discuss drugs identified as potential UPR-modifying therapeutic agents—in particular the licensed antidepressant trazodone—and we review epidemiological and trial data from their use in human populations. Finally, we explore future directions for investigating the potential benefit of using trazodone or similar UPR-modulating compounds for disease modification in patients with dementia.
登录
查看更多内容
影响因子：
6.3
作者：
Bronskill, Susan E.;Campitelli, Michael A.;Maxwell, Colleen J.
通讯作者：
Maxwell, Colleen J.
影响因子：
4.2
作者：
Devi L;Ohno M
通讯作者：
Ohno M
影响因子：
4.2
作者：
Das, Melanie M.;Svendsen, Clive N.
通讯作者：
Svendsen, Clive N.
影响因子：
14
作者：
通讯作者：
--
影响因子：
12.7
作者：
Duran-Aniotz, Claudia;Cornejo, Victor Hugo;Hetz, Claudio
通讯作者：
Hetz, Claudio