IMO, this paper below is also important for ATH with an iron chelator ATH434. Sirtuins get activated by ATP produced in the mitochondria. Iron overload will hamper ATP, NAD+ (energy) production as has been demonstrated in many studies. ATH434 reduced alpha-synuclein and death of neurons ( Finkelstein et al).
So the less there is energy, the less there will be sirtuins as Sirt3.

My guess is that ATH434 has also increased Sirt3 because the test animals gained their mobility in the ATH434 studies: Beauchamp et al 2022: "ATH434 was able to prevent the development of hyposmia in young tau-/- mice, which coincided with a reduction in bulbar iron and copper levels, an increase in synaptophysin, and a reduction in soluble α-synuclein. ATH434 was able to prevent the development of motor impairment in aged tau-/- mice, which coincided with a reduction in iron levels and reduced neurodegeneration in the substantia nigra".

But this paper below from Canada explains the role of SIRT3 and does it in a very nice way. Here is the abstract

Neurobiol Dis

. 2023 Sep 11;106287.

doi: 10.1016/j.nbd.2023.106287. Online ahead of print.

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

Dennison Trinh ¹, Ahmad R Israwi ¹, Harsimar Brar ², Jose E A Villafuerte ², Ruella Laylo ², Humaiyra Patel ², Sabika Jafri ², Lina Al Halabi ², Shaumia Sinnathurai ², Kiran Reehal ², Alyssa Shi ², Vayisnavei Gnanamanogaran ², Natalie Garabedian ², Drake Thrasher ³, Philippe P Monnier ⁴, Laura A Volpicelli-Daley ³, Joanne E Nash ⁵

Affiliations collapse

Affiliations

• ¹Department of Biological Sciences, University of Toronto Scarborough, Toronto, Ontario, Canada; Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada.
• ²Department of Biological Sciences, University of Toronto Scarborough, Toronto, Ontario, Canada.
• ³Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA.
• ⁴Krembil Research Institute, University Health Network, Toronto, Ontario, Canada.
• ⁵Department of Biological Sciences, University of Toronto Scarborough, Toronto, Ontario, Canada; Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada. Electronic address: [email protected].

• PMID: 37704058

DOI: 10.1016/j.nbd.2023.106287

Abstract

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 SIRT3^H248Y was transduced, demonstrating the importance of SIRT3 deacetylation in reducing α-synuclein aggregation. These studies confirm show the that there is a clear difference in SIRT3 levels in subjects with Parkinson's disease compared 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.