Parkinson's disease pathology is directly correlated to SIRT3 in human subjects and animal models: Implications for AAV.SIRT3-myc as a disease-modifying therapy

SIRT3 疾病 帕金森病 线粒体 生物 乙酰化 神经科学 医学 内科学 内分泌学 癌症研究 锡尔图因 细胞生物学 生物化学 基因
作者
Dennison Trinh,Ahmad R. Israwi,Harinder Brar,Jose E.A. Villafuerte,Ruella Laylo,Himali Patel,S. M. Wasim Jafri,Lina Al Halabi,Shaumia Sinnathurai,Kiran Reehal,Aibin Shi,Vayisnavei Gnanamanogaran,N. Garabédian,Drake R. Thrasher,Philippe P. Monnier,Laura A. Volpicelli‐Daley,Joanne E. Nash
出处
期刊:Neurobiology of Disease [Elsevier BV]
卷期号:187: 106287-106287
标识
DOI:10.1016/j.nbd.2023.106287
摘要

In Parkinson's disease (PD), post-mortem studies in affected brain regions have demonstrated a decline in mitochondrial number and function. This combined with many studies in cell and animal models suggest that mitochondrial dysfunction is central to PD pathology. We and others have shown that the mitochondrial protein deacetylase, SIRT3, has neurorestorative effects in PD models. In this study, to determine whether there is a link between PD pathology and SIRT3, we analysed SIRT3 levels in human subjects with PD, and compared to age-matched controls. In the SNc of PD subjects, SIRT3 was reduced by 56.8 ± 15.5% compared to control, regardless of age (p < 0.05, R = 0.6539). Given that age is the primary risk factor for PD, this finding suggests that reduced SIRT3 may contribute to PD pathology. Next, we measured whether there was a correlation between α-synuclein and SIRT3. In a parallel study, we assessed the disease-modifying potential of SIRT3 over-expression in a seeding model of α-synuclein. In PFF rats, infusion of rAAV1.SIRT3-myc reduced abundance of α-synuclein inclusions by 30.1 ± 18.5%. This was not observed when deacetylation deficient SIRT3H248Y was transduced, demonstrating the importance of SIRT3 deacetylation in reducing α-synuclein aggregation. These studies confirm that there is a clear difference in SIRT3 levels in subjects with PD compared to age-matched controls, suggesting a link between SIRT3 and the progression of PD. We also demonstrate that over-expression of SIRT3 reduces α-synuclein aggregation, further validating AAV.SIRT3-myc as a potential disease-modifying solution for PD.
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