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
Bibliographic record
Abstract
Abstract Degeneration of the dopaminergic nigro-striatal pathway and presence of Lewy bodies are pathological hallmarks of Parkinson’s disease (PD). Postmortem studies in human tissue have also demonstrated that a decline in mitochondrial number and function is also central to PD pathology. Sirtuin 3 (SIRT3) is a mitochondrial protein deacetylase which has been linked with longevity and cytoprotective effects. SIRT3 serves as a metabolic sensor and regulates mitochondrial homeostasis and oxidative stress, which likely stabilises telomere integrity, delaying senescence. Previously, we have shown that over-expression of SIRT3 rescues motor function and prevents degeneration of dopaminergic neurons in a virally over-expressing mutant (A53T)-α-synuclein model of PD. In the present study, we show that in the substantia nigra pars compacta (SNc) of human subjects, SIRT3 levels are negatively correlated with age (p<0.05, R=0.6539). In the hippocampus, there was no correlation between SIRT3 levels and age. In human subjects with PD, SIRT3 was reduced by 56.8±15.5% and 34.0±5.6% in the SNc and hippocampus respectively regardless of age. Given that age is the primary risk factor for PD, this finding suggests that reduced SIRT3 may be a causative factor contributing to PD pathology. Next in human subjects with PD, we measured whether there was a correlation between the amount of aggregated α-synuclein and SIRT3 levels by measuring immunofluorescence of phosphorylated α-synuclein (p-syn), which is a marker for Lewy bodies. Interestingly, in the hippocampus, but not SNc, there was a positive correlation between SIRT3 and p-syn levels, despite p-syn being reduced compared to control. Next using an α-synuclein seeding rat model of PD, we assessed the disease-modifying effects of viral-mediated SIRT3 infusion. Six months following infusion of α-synuclein pre-formed fibrils (PFF) into the SNc, there was 38.8±4.5% loss of TH-positive neurons, impaired striatal dopamine metabolism and pathological α-synuclein throughout the brain. Phosphorylated-α-synuclein immunoreactivity was present in the SNc, olfactory tubercle, striatum, amygdala, hippocampus and motor cortex. In PD subjects, synuclein positive aggregates have also been reported in these brain regions. In PFF rats, infusion of rAAV1.SIRT3-myc in the SNc reduced abundance of α-synuclein inclusions in the SNc by 30.1±18.5% which was not seen when deacetylation deficient SIRT3 H248Y was transduced. This demonstrates the importance of SIRT3deacetylation in reducing α-synuclein aggregation. However, while SIRT3 transduction reduced aggregation in the SNc, it had no significant effect on phosphorylated-α-synuclein levels in other brain regions. These studies confirm that SIRT3 is directly correlated with senescence and aging in humans. We also provide evidence that reduced SIRT3 contributes to the pathology of clinical PD. Finally, by showing that over-expression of SIRT3 prevents α-synuclein aggregation through de-acetylation-dependent mechanisms, we further validate AAV1.SIRT3-myc as a potential disease-modifying therapy for PD.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".