SIRT1 pathway in Parkinson's disease: a faraway snapshot but so close

Abstract

Silent information regulator (SIRT) has distinctive enzymatic activities and physiological functions to control cell-cycle progression, gene expression, and DNA stability by targeting histone and non-histone proteins. SIRT1 enhances synaptic formation and synaptic activity, and therefore, can reduce the progression of various degenerative brain diseases including Parkinson's disease (PD). SIRT1 activity is decreased by aging with a subsequent increased risk for the development of degenerative brain diseases. Inhibition of SIRT1 promotes inflammatory reactions since SIRT1 inhibits transcription of nuclear factor kappa B (NF-κB) which also inhibits SIRT1 activation via activation of microRNA and miR-34a which reduce NAD synthesis. SIRT1 is highly expressed in microglia as well as neurons, and has antioxidant and anti-inflammatory effects. Therefore, this review aimed to find the possible role of SIRT1 in PD neuropathology. SIRT1 has neuroprotective effects; therefore, downregulation of SIRT1 during aging promotes p53 expression and may increase the vulnerability of neuronal cell deaths. PD neuropathology is linked with the sequence of inflammatory changes and the release of pro-inflammatory cytokines due to the activation of inflammatory signaling pathways. In addition, oxidative stress, inflammatory disorders, mitochondrial dysfunction, and apoptosis contribute mutually to PD neuropathology. Thus, SIRT1 and SIRT1 activators play a crucial role in the mitigation of PD neuropathology through the amelioration of oxidative stress, inflammatory disorders, mitochondrial dysfunction, apoptosis, and inflammatory signaling pathways.

Keywords: Apoptosis; Inflammatory disorders; Mitochondrial dysfunction; Oxidative stress; Parkinson’s disease; Silent information regulator.

Fig. 1

Role of SIRT1 in cellular functions. Adenosine monophosphate protein kinase (AMPK) is activated by oxidative stress leading to the enhancement of mitochondrial biogenesis, fatty acid oxidation, and improvement of insulin sensitivity. AMPK increases the NADH ratio leading to activation of SIRT1 which via expression of liver kinase B (LKB1) stimulates AMPK expression. Activated SIRT1 stimulates peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1α) leading to improvement of mitochondrial biogenesis, antioxidant effects, and regulation of glucose as well as lipid homeostasis. As well, activation of SIRT1 inhibits expression of p53 and transcription of nuclear factor kappa B (NF-κB) with subsequent inhibition of apoptosis and inflammation, respectively

Fig. 2

SIRT1 and oxidative stress. Oxidative stress inhibits the expression of SIRT1. SIRT1 deacetylases different targets with activation of the endothelial nitric oxide synthase (eNOS) and peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1α) with inhibition of p53, forkhead box O1 (FOXO1), and nuclear factor kappa B (NF-κB). SIRT1 via epigenetic effects activates kruppel-like factor 2 (KLF2) and inhibits p66shc gene expression

Fig. 3

Mitochondrial dysfunction and development of Parkinson’s disease (PD). Calcium imbalance, altered mitochondrial dynamics, impaired biogenesis, oxidative stress, defective mitophagy, impaired mitochondrial trafficking, and dysfunctional respiratory chain lead to development of mitochondrial dysfunction with subsequent progression of PD due to degeneration of the dopaminergic neurons

Fig. 4

SIRT1 inhibitor, AG1031, and development of apoptosis. SIRT1 inhibits the expression of p53 as well as the development and progression of apoptosis. The SIRT1 inhibitor, AG1031, promotes apoptosis through uncontrolled p53 activation. p53 induces apoptosis directly by triggering the development of the oxidative stress or indirectly through activation of the pro-apoptotic Bax gene which stimulates cytochrome c (cyto c) and caspase-9 with subsequent activation of caspase-3 leading to apoptosis

Fig. 5

Role of NF-κB in the development of PD. Extracellular stimuli through activation of TLR4 in the presence of CD44 promote NF-κB activation and the release of pro-inflammatory cytokines with development of PD. However, deficiency of CD44 attenuates NF-κB activation and the development of neuroinflammation in PD

Fig. 6

CD38 and SIRT1 pathway. CD38 deficiency promotes NAD and SIRT1 activation which inhibits the expression of Ac-K310 and NF-κB with subsequent inhibition of the release of the pro-inflammatory cytokines

Fig. 7

Role of metformin in activation of SIRT1

Fig. 8

Effects of resveratrol on SIRT1 and AMPK expression