Brittany Lively

Background: Parkinson’s disease (PD) is a major neurodegenerative disorder characterized by dopaminergic (DA) neuronal death in the substantia nigra pars compacta (SNc). PD affects 6.1 million people as of 2016, however, current treatments for PD are based on symptom management and do not alter disease progression, which has resulted in an urgent need for neuroprotective treatments.^{1, 2} The vast majority of PD cases are idiopathic, caused by exposure to toxins such as pesticides or predisposing head injuries.^{1, 2} SNc DA neuronal death results from α-synuclein aggregation, an important component of Lewy bodies responsible for the pathogenesis of PD, which is exacerbated by SIRT2.^{2, 3} Based on this, recent studies have explored ways of inhibiting SIRT2 to lessen SNc DA neuron loss in order to slow the PD progression. Specific strategies include the alteration of the activity of enzymes such as GSK3β or Cdk5 or through the use of micro RNAs.^{4, 5, 6, 7}

Objectives: Because of the emerging importance of SIRT2 in PD pathogenesis, we investigate strategies for the inhibition of SIRT2 as a method to alleviate the death of DA neurons in PD.

Search Methods: An online search within the PubMed database was conducted from 2018 to 2024 using the following keywords: “Parkinson’s disease”, “SIRT2”, “sirtuin”, “neuroprotective”.

Results: Treatment of SH-SY5Y cells with the PD toxin, 6-hydroxydopamine (6-OHDA) increased the activity of GS3Kβ and levels of SIRT2 phosphorylation.⁴ In this model, GS3Kβ blockage via SB216763 decreased SIRT2 phosphorylation, increased tubulin acetylation, and increased viability in 6-OHDA-treated SH-SY5Y cells.⁴ Mutants constructed to mimic the phosphorylated and dephosphorylated states of SIRT2 showed that phosphorylated SIRT2 can decrease α-tubulin acetylation and worsen cell death, while the dephosphorylated state alleviated these effects.⁴ LC-MS after kinase assay showed SIRT2 is also phosphorylated by Cdk5 at Ser331 and Ser335. Furthermore, inhibition of Cdk5 with roscovitine suppressed SIRT2 nuclear translocation.⁵ Peptide, Myr-SIRT2_328-339 designed to competitively inhibit Cdk5 SIRT2 phosphorylation was found to suppress MPP+ induced SIRT2 nuclear translocation and reduce cell mortality in primary cultured neurons. Importantly, Myr-SIRT2_328-339 also reduced SNc DA neuron loss and improved motor function in MPTP-treated mice.⁵ In the context of another strategy to inhibit SIRT2, microRNA-486-3P was found to bind to SIRT2 at its 3’ UTR and q-RT-PCR and decrease SIRT2 mRNA and protein expression.⁶ In addition, miR-486-3p transfection into SH-SY5Y cells increased α-tubulin acetylation, reduced α-synuclein aggregation, and increased TH+ cells, which suggests an alleviation of neuronal injury.⁶ Interestingly, treatment of SH-SY5Y cells with another microRNA (miR), microRNA-212-5P decreased SIRT2 expression while leaving SIRT1 unchanged, and in MPTP-treated mice, this miR lessened SIRT2 elevation and reduced loss of TH+ neurons in the SNpc, which suggests the potential use of miRs in mitigating SNc DA neuron loss.⁷

Conclusion: Studies have found that inhibition of SIRT2 increases α-tubulin acetylation, reduces α-synuclein aggregation, and alleviates the accelerated cell death in cellular models of PD. Additionally, SIRT2 inhibition in MPTP-induced PD mouse model reduced TH+ neuron loss in the SNc and improved motor function. In conclusion, the inhibition of Cdk5 or GSK3β or treatment with microRNAs could function as possible neuroprotective therapeutic options in PD.

Works Cited:

1. Armstrong MJ, Okun MS. Diagnosis and Treatment of Parkinson Disease: A Review. JAMA. 2020;323(6):548-560. doi:10.1001/jama.2019.22360
2. Bloem BR, Okun MS, Klein C. Parkinson’s disease. Lancet. 2021;397(10291):2284-2303. doi:10.1016/S0140-6736(21)00218-X
3. Liu Y, Zhang Y, Zhu K, Chi S, Wang C, Xie A. Emerging Role of Sirtuin 2 in Parkinson’s Disease. Front Aging Neurosci. 2020;11:372. Published 2020 Jan 10. doi:10.3389/fnagi.2019.00372
4. Liu S, Zhou Z, Zhang L, Meng S, Li S, Wang X. Inhibition of SIRT2 by Targeting GSK3β-Mediated Phosphorylation Alleviates SIRT2 Toxicity in SH-SY5Y Cells. Front Cell Neurosci. 2019;13:148. Published 2019 Apr 24. doi:10.3389/fncel.2019.00148
5. Yan J, Zhang P, Tan J, et al. Cdk5 phosphorylation-induced SIRT2 nuclear translocation promotes the death of dopaminergic neurons in Parkinson’s disease. NPJ Parkinsons Dis. 2022;8(1):46. Published 2022 Apr 20. doi:10.1038/s41531-022-00311-0
6. Wang Y, Cai Y, Huang H, et al. miR-486-3p Influences the Neurotoxicity of a-Synuclein by Targeting the SIRT2 Gene and the Polymorphisms at Target Sites Contributing to Parkinson’s Disease. Cell Physiol Biochem. 2018;51(6):2732-2745. doi:10.1159/000495963
7. Sun S, Han X, Li X, et al. MicroRNA-212-5p Prevents Dopaminergic Neuron Death by Inhibiting SIRT2 in MPTP-Induced Mouse Model of Parkinson’s Disease. Front Mol Neurosci. 2018;11:381. Published 2018 Oct 11. doi:10.3389/fnmol.2018.00381