Sirtuins and Their Implications in Neurodegenerative Diseases from a Drug Discovery Perspective

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.