Abstract
Sirtuins are a class of histone deacetylases (HDACs) that have been shown to regulate a range of pathophysiological processes such as cellular aging, inflammation, metabolism, and cell proliferation. There are seven mammalian Sirtuins (SIRT1-7) that play important roles in stress response, aging, and neurodegenerative diseases. However, the location and function of Sirtuins in neurons are not well defined. This study assessed the retinal expression of Sirtuins in mice, rats, and humans and measured the expression of Sirtuins in aged and injured retinas. Expression of all 7 Sirtuins was confirmed by Western blot and Real-Time PCR analysis in all three species. SIRT1 is highly expressed in mouse, rat, and human retinas, whereas SIRT2-7 expression was relatively lower in human retinas. Immunofluorescence was also used to examine the expression and localization of Sirtuins in rat retinal neurons. Importantly, we demonstrate a marked reduction of SIRT1 expression in aged retinal neurons as well as retinas injured by acute ischemia-reperfusion. On the other hand, none of the other Sirtuins exhibit any significant age-related changes in expression except for SIRT5, which was significantly higher in the retinas of adults compared to both young and aged rats. Our work presents the first composite analysis of Sirtuins in the retinal neurons of mice, rats, and humans, and suggests that increasing the expression and activity of SIRT1 may be beneficial for the treatment of glaucoma and other age-related eye dysfunction.
Highlights
The Sirtuins (SIRT) are an NAD+ dependent class III histone deacetylases (HDACs) that share extensive homology with the yeast HDAC Silent Information Regulator 2 (Sir2) (Satoh et al, 2011)
A SIRT1 fragment is present in the euchromatin, SIRT6 is present in the heterochromatin, and SIRT7 exists in the nucleolus, whereas SIRT2 is predominantly located in the cytoplasm and SIRT3, SIRT4, and SIRT5 are mitochondrial Sirtuins (Braidy et al, 2015)
Our results demonstrate that the protein levels of the Sirtuins in mouse retinas descend in the following order: SIRT3, SIRT1, SIRT5, SIRT4, SIRT7, SIRT2, and SIRT6 (Figure 2H)
Summary
The Sirtuins (SIRT) are an NAD+ dependent class III HDACs that share extensive homology with the yeast HDAC Silent Information Regulator 2 (Sir2) (Satoh et al, 2011). SIRT/Sir activity is crucial for lifespan extension by responding to metabolic and other environmental stresses. Seven Sir homologues (SIRT1-7) have been identified. They demonstrate primarily histone deacetylase (SIRT1, SIRT2, SIRT3, and SIRT5) or monoribosyltransferase activity (SIRT4 and SIRT6), which target histone and various non-histone proteins in distinct subcellular locations. A SIRT1 fragment is present in the euchromatin, SIRT6 is present in the heterochromatin, and SIRT7 exists in the nucleolus, whereas SIRT2 is predominantly located in the cytoplasm and SIRT3, SIRT4, and SIRT5 are mitochondrial Sirtuins (Braidy et al, 2015)
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