SIRT1 and SIRT2: emerging targets in neurodegeneration

Abstract

Sirtuins are NAD-dependent protein deacetylases known to have protective effects against age-related diseases such as cancer, diabetes, cardiovascular and neurodegenerative diseases. In mammals, there are seven sirtuins (SIRT1-7), which display diversity in subcellular localization and function. While SIRT1 has been extensively investigated due to its initial connection with lifespan extension and involvement in calorie restriction, important biological and therapeutic roles of other sirtuins have only recently been recognized. Here, we review the potential roles and effects of SIRT1 and SIRT2 in neurodegenerative diseases. We discuss different functions and targets of SIRT1 and SIRT2 in a variety of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's Disease (HD). We also cover the role of SIRT1 in neuronal differentiation due to the possible implications in neurodegenerative conditions, and conclude with an outlook on the potential therapeutic value of SIRT1 and SIRT2 in these disorders.

Figure 1. The targets and interacting partners of SIRT1

SIRT1 has many targets that play roles in different molecular pathways including neuronal protection, inflammation, stress resistance, mitochondrial biogenesis, fatty acid oxidation and mobilization, insulin secretion, glucose production and lipid homeostasis. SIRT1 is activated by CR, NAD biosynthesis and small molecule sirtuin activators (STACs).

Figure 2. SIRT1 and SIRT2 in neurodegeneration

As a result of numerous publications, SIRT1 seems to have protective effects against AD, PD and HD. Therefore, activating SIRT1 could be beneficial against these diseases. On the other hand, deletion of SIRT2 seems to be protective against PD. Because there is conflicting data regarding the effect of SIRT2 on HD and lack of data regarding the effect of SIRT2 on AD, the roles of SIRT2 in HD and AD remain unclear.