School of Science, Monash University Malaysia Campus, Jalan Lagoon Selatan, Bandar Sunway, 47500 Selangor, Malaysia.
Faculty of Applied Sciences, Tunku Abdul Rahman University College (TARUC), Jalan Genting Kelang, 53300 Kuala Lumpur, Malaysia.
ACS Chem Neurosci. 2020 Dec 16;11(24):4073-4091. doi: 10.1021/acschemneuro.0c00696. Epub 2020 Dec 5.
Sirtuins are class III histone deacetylase (HDAC) enzymes that target both histone and non-histone substrates. They are linked to different brain functions and the regulation of different isoforms of these enzymes is touted to be an emerging therapy for the treatment of neurodegenerative diseases (NDs), including Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). The level of sirtuins affects brain health as many sirtuin-regulated pathways are responsible for the progression of NDs. Certain sirtuins are also implicated in aging, which is a risk factor for many NDs. In addition to SIRT1-3, it has been suggested that the less studied sirtuins (SIRT4-7) also play critical roles in brain health. This review delineates the role of each sirtuin isoform in NDs from a disease centric perspective and provides an up-to-date overview of sirtuin modulators and their potential use as therapeutics in these diseases. Furthermore, the future perspectives for sirtuin modulator development and their therapeutic application in neurodegeneration are outlined in detail, hence providing a research direction for future studies.
Sirtuins 是 III 类组蛋白去乙酰化酶 (HDAC) 酶，可靶向组蛋白和非组蛋白底物。它们与不同的大脑功能有关，这些酶的不同同工型的调节被吹捧为治疗神经退行性疾病 (NDs) 的新兴疗法，包括帕金森病 (PD)、阿尔茨海默病 (AD) 和肌萎缩侧索硬化症 (ALS)。由于许多受 sirtuins 调节的途径负责 NDs 的进展，因此 sirtuins 的水平会影响大脑健康。某些 sirtuins 也与衰老有关，衰老也是许多 NDs 的一个风险因素。除了 SIRT1-3 之外，研究较少的 sirtuins（SIRT4-7）也被认为在大脑健康中发挥着关键作用。从疾病为中心的角度来看，本综述阐述了每种 sirtuin 同工型在 NDs 中的作用，并提供了 sirtuin 调节剂及其在这些疾病中作为治疗剂的潜在用途的最新概述。此外，还详细概述了 sirtuin 调节剂开发及其在神经退行性变中的治疗应用的未来前景，从而为未来的研究提供了研究方向。
