Abstract
Sirtuins are NAD+ dependent histone deacetylases (HDAC) that play a pivotal role in neuroprotection and cellular senescence. SIRT1-7 are different homologs from sirtuins. They play a prominent role in many aspects of physiology and regulate crucial proteins. Modulation of sirtuins can thus be utilized as a therapeutic target for metabolic disorders. Neurological diseases have distinct clinical manifestations but are mainly age-associated and due to loss of protein homeostasis. Sirtuins mediate several life extension pathways and brain functions that may allow therapeutic intervention for age-related diseases. There is compelling evidence to support the fact that SIRT1 and SIRT2 are shuttled between the nucleus and cytoplasm and perform context-dependent functions in neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). In this review, we highlight the regulation of SIRT1 and SIRT2 in various neurological diseases. This study explores the various modulators that regulate the activity of SIRT1 and SIRT2, which may further assist in the treatment of neurodegenerative disease. Moreover, we analyze the structure and function of various small molecules that have potential significance in modulating sirtuins, as well as the technologies that advance the targeted therapy of neurodegenerative disease.
Highlights
Sirtuins (Silent information regulator proteins) are essential anti-aging factors that are conserved in all kingdoms of living organisms, from bacteria to the human they have nearly identical structures and catalytic functions (Vassilopoulos et al, 2011)
In this review we describe the structural aspects of both SIRT1 and SIRT2 to understand the mechanism of sirtuin modulation in neurodegenerative diseases, presenting activators and inhibitors that have either been confirmed or postulated to bind to the selectivity pocket, and provide an outlook regarding mechanistic
Mammalian sirtuins are a class of critical factors that have been shown to play important roles in the homeostasis of tissues and organs, as well as in the regulation of numerous cellular processes
Summary
Sirtuins (Silent information regulator proteins) are essential anti-aging factors that are conserved in all kingdoms of living organisms, from bacteria to the human they have nearly identical structures and catalytic functions (Vassilopoulos et al, 2011). Initial studies showed that as a result of RSV treatment, cell survival in animal models increased by the stimulation of p53 deacetylation by SIRT1 (Howitz et al, 2003). The in vitro studies performed by Biella G et al suggested that inhibition of SIRT2 by AGK2 and AK7 reduced the Aβ production in H4-SW neuroglioma cells and modified the APP proteolytic processing, leading to a reduction of soluble Aβ and an increase of soluble α-amyloid protein in two AD transgenic mouse models (3xTgAD and APP23).
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