The Critical Role of SIRT1 in Parkinson’s Disease: Mechanism and Therapeutic Considerations

Abstract

Silence information regulator 1 (SIRT1), a member of the sirtuin family, targets histones and many non-histone proteins and participates in various physiological functions. The enzymatic activity of SIRT1 is decreased in patients with Parkinson's disease (PD), which may reduce their ability to resist neuronal damage caused by various neurotoxins. As far as we know, SIRT1 can induce autophagy by regulating autophagy related proteins such as AMP-activated protein kinase, light chain 3, mammalian target of rapamycin, and forkhead transcription factor 1. Furthermore, SIRT1 can regulate mitochondrial function and inhibit oxidative stress mainly by maintaining peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in a deacetylated state and thus maintaining a constant level of PGC-1α. Other studies have demonstrated that SIRT1 may play a role in the pathophysiology of PD by regulating neuroinflammation. SIRT1 deacetylases nuclear factor-kappa B and thus reduces its transcriptional activity, inhibits inducible nitric oxide synthase expression, and decreases tumor necrosis factor-alpha and interleukin-6 levels. SIRT1 can also upregulate heat shock protein 70 by deacetylating heat shock factor 1 to increase the degradation of α-synuclein oligomers. Few studies have focused on the relationship between SIRT1 single nucleotide polymorphisms and PD risk, so this topic requires further research. Based on the neuroprotective effects of SIRT1 on PD, many in vitro and in vivo experiments have demonstrated that some SIRT1 activators, notably resveratrol, have potential neuroprotective effects against dopaminergic neuronal damage caused by various neurotoxins. Thus, SIRT1 plays a critical role in PD development and might be a potential target for PD therapy.

Recent Insights into the Interplay of Alpha-Synuclein and Sphingolipid Signaling in Parkinson’s Disease

“…Another toxic effect elicited by Sphk1 inhibition and "sphingolipid biostat" disturbances is oxidative stress. Therefore, anti-oxidative agents, like Sirt1 activators, may be significantly promising in PD therapy, since Sirt1 may also reduce ASN accumulation by regulating its autophagy [181,182].…”

Formyl Peptide Receptor (FPR)1 Modulation by Resveratrol in an LPS-Induced Neuroinflammatory Animal Model

“…Resveratrol (trans-3,4′,5-trihydroxystilbene) is a polyphenol present in large amount in red wine, for which many pharmacologic properties, as well as cardioprotection, antioxidant and anticancer activity, are associated with its beneficial effects. It has been widely reported that this polyphenol is correlated with neuroprotective properties both in vitro and in vivo and has been also proposed to exert anti-inflammatory effects in several systems by inducing the expression of sirtuin1 (SIRT1), including in activated microglia [ 17 , 18 , 19 ].…”

Cannabidiol Induces Autophagy to Protects Neural Cells From Mitochondrial Dysfunction by Upregulating SIRT1 to Inhibits NF-κB and NOTCH Pathways

“…Mitochondrial biogenesis is a key process in the maintenance of mitochondrial mass, SIRT1 is the main regulator of mitochondrial biogenesis ( Mao et al, 2020 ). The increase of SIRT1 has been considered as a therapeutic strategy for PD, previous research showed that SIRT1 has neuroprotective effects in both in vivo and in vitro PD models ( Li et al, 2020 ). Simultaneously, SIRT1 was significantly downregulated in neurons treatmented with rotenone or MPP + ( Chen et al, 2019 ).…”