Does anyone know anything about this?
Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of GT-02287 in Parkinson’s Disease
https://clinicaltrials.gov/study/NCT06732180
From:
The Fragile Future of American Science
On February 7, 2025, the National Institutes of Health announced a cap of 15% on reimbursement of Facilities & Administration (F&A) research grant costs, which cover equipment and facilities, maintenance and compliance, data processing, and many other essential needs that make research possible. The proposed cap could mean an estimated loss of almost $200 million annually in research funding at Duke and significantly hinder or halt scientific and biomedical research in many critical areas. The order is currently on hold pending legal review, but the situation remains fluid and uncertain, and review of federal research grants has slowed dramatically.
Laurie H. Sanders, PhD, associate professor in neurology and pathology, conducts research on Parkinson’s disease. Her lab has developed a method, based on mitochondrial DNA damage, that can detect Parkinson’s disease in its early stages with a simple blood test. Her research has the potential not only to enable early diagnosis and intervention before significant neurological damage occurs, but also to help identify therapeutic targets to reverse or halt damaged mitochondrial DNA and the disease process. Parkinson’s disease, a progressive age-related brain disorder, afflicts 10 million people worldwide and is the second-most common neurodegenerative disease after Alzheimer’s.
What’s the status of your research now?
Sanders: Obviously, we’re really excited about our initial research and the importance of being able to differentiate very early on between people with Parkinson’s disease and people without. But this is just the beginning. While I would consider it a major advance, we still have a lot to do.
For example, we need to learn how these biomarkers change over time. In order to scale this up for clinical trials, we need to know how these biomarkers will change over the lifespan of a clinical trial. We also want to know whether these same changes to mtDNA are involved in related conditions like ALS and Huntington’s disease. And we want to understand what’s driving DNA damage in the first place, because then we might be able to target that process with new therapeutics.
So there are questions yet to be answered, and we’re excited to continue working to answer them and develop new therapies for Parkinson’s. But we can’t do it alone. My current grant ends in August. I’ve submitted a grant proposal to continue our work, but right now they’re not even reviewing grants, much less approving them.
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So there is already evidence that mtDNA damage is linked to PD.
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Yes, Tzoulis in Norway is studying this extensively (that’s why he’s interested in melatonin), some subtypes might be more affected than others:
- Defective mitochondrial DNA homeostasis in the substantia nigra in Parkinson disease | Nature Communications (“We show that in dopaminergic substantia nigra neurons of healthy individuals, mtDNA copy number increases with age, maintaining the pool of wild-type mtDNA population in spite of accumulating deletions. This upregulation fails to occur in individuals with Parkinson disease, however, resulting in depletion of the wild-type mtDNA population. By contrast, neuronal mtDNA point mutational load is not increased in Parkinson disease. Our findings suggest that dysregulation of mtDNA homeostasis is a key process in the pathogenesis of neuronal loss in Parkinson disease.”)
- https://www.sciencedirect.com/science/article/pii/S1567724916300137 (“Our findings demonstrate that dopaminergic neurons of the substantia nigra are specifically vulnerable to defective mtDNA replication/repair or quality control and not to primary point mutations of mtDNA. These results support the hypothesis that accumulating somatic mtDNA damage plays an important role in neurodegeneration.”)
- Mitochondrial complex I deficiency stratifies idiopathic Parkinson’s disease | Nature Communications (“In contrast, the non-CI deficient (nCI-PD) subtype exhibits no evidence of mitochondrial impairment outside the dopaminergic substantia nigra and has a predilection for a tremor dominant phenotype.”)
- Neuronal complex I deficiency occurs throughout the Parkinson’s disease brain, but is not associated with neurodegeneration or mitochondrial DNA damage | Acta Neuropathologica
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Interaction Between Traffic-Related Air Pollution and Parkinson Disease Polygenic Risk Score 2025
Genetic and environmental factors are linked to Parkinson disease (PD), but the role of genetic susceptibility in the association between traffic-related air pollution (TRAP) and PD remains unclear.
To assess the gene-environment interaction between the polygenic risk score (PRS) for PD and long-term TRAP exposure and to estimate the joint effect with PD risk.
Meta-analytical estimates suggest that both higher PRS and increased TRAP exposure increased PD risk, with an interaction effect estimate of 1.06 (95% CI, 1.00-1.12). Joint effect analysis indicated that individuals with both high PRS and high TRAP exposure were at greatest risk of PD (odds ratio, 3.05; 95% CI, 2.23-4.19) compared with the reference group with a low PRS and low TRAP exposure, suggesting a synergistic effect.
Just published @John_Hemming (Newcastle University): A reciprocal relationship between markers of genomic DNA damage and alpha-synuclein pathology in dementia with Lewy bodies 2025
DNA damage and DNA damage repair (DDR) dysfunction are insults with broad implications for cellular physiology and have been implicated in various neurodegenerative diseases. Alpha-synuclein (aSyn), a pre-synaptic and nuclear protein associated with neurodegenerative disorders known as synucleinopathies, has been associated with DNA double strand break (DSB) repair.
DNA damage was also present in cortical tissue from presymptomatic A30P mice, demonstrating it is an early insult closely associated with pathogenic aSyn.
The observed cellular pathology was consistent with nuclear upregulation of associated DDR proteins, particularly those involved in base excision repair and DSB repair pathways.
Ultimately, our study supports the hypothesis of a reciprocal relationship between aSyn pathology and nuclear DNA damage and highlights a potential underlying role for DNA damage in pathological mechanisms relevant to DLB, as well as other synucleinopathies, opening novel possibilities for diagnosis and treatment.
Whilst some studies support DSB repair to be more strongly affected by aSyn pathology, our measures of SSBs in A30P mice confirm an appreciable increase in XRCC1 compared to controls, although non-significant. Given that unresolved SSB can generate DSBs [66], perhaps initial DDR dysfunctions may occur in SSB repair, later progressing to an accumulation of DSBs and a failure of their repair. It is equally plausible, however, that in addition to the failure of DSBs repair, early mitochondrial dysfunction and increased oxidative stress may independently drive an increase in SSBs [3]. Establishing a more detailed timeline of DNA damage in the context of organelle specific dysfunction will be an important focus of future research.
The data suggests a reciprocal relationship, whereby aSyn pathology induces DNA damage, which in turn generate ectopic cytoplasmic genomic material, capable of facilitating cytoplasmic aSyn aggregation.
Nevertheless, the established early occurrence of DNA damage and the delineation of disease dependent DDR changes, highlights DNA damage and its repair as prominent targets for future therapeutic development.
Oxytocin may help with that. We started doing daily nasal sprays of Oxytocin (15iu = 26mcg) 3 times a day about a month ago.
The organization of the hypothalamus and posterior pituitary suggests that oxytocin and AVP could exert their effects on social and cognitive function through a combination of central and peripheral regulation of glymphatic function, where blood-borne peptides change vascular tone and interstitial fluid-mediated peptidergic signaling changes synaptic tone.
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What benefits and side effects, if any, are you seeing from the Oxytocin spray?
Are you cuddling more 
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I wonder if we can have a unified framework that can integrate and explain:
- The dual-hit hypothesis: Parkinson's disease - #468 by adssx
- The reciprocal relationship between DNA damage and alpha-syn aggregation: Parkinson's disease - #711 by adssx
For instance, a three-stage pathogenesis model:
- Priming Phase (silent, early, pre-symptomatic): α-syn accumulation (genetic predisposition, aging, mitochondrial dysfunction, or environmental neurotoxins) OR DNA damage (environmental genotoxins, mitochondrial dysfunction, viral infections, aging)
- Triggering Phase (the second hit that converts vulnerability into pathology): Immune activation / inflammation
- Propagation Phase (the feedback loop): Reciprocal reinforcement between α-syn aggregation ↔ DNA damage ↔ inflammation
?
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I really like that model, Antoine. It has a lot of explanatory power and fits the data pretty well. If I were to go by intuition, I think it’s likely to be correct - but then again, I’ve had this kind of model turning in my head for a long time. It fits a lot, including the cholesterol/statin PD contradictions (which btw. I’m still working on, it’s a very deep rabbit hole, unfortunately).
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I’m a cuddle monster!!
But yes, I do find some benefit to my demeanor, I’m not quite as mean LoL!
One of the things that Bryan J talks about is Nocturnal penile tumescence (NPT). This is an indicator of “age”. Over the last 5 years I’ve “noticed” it doesn’t seem to happen as much. But it has risen, to a more noticeable level in the past couple months.
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Produced by ChatGPT 4.5 after feeding it the three papers 
I like it as well.
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McGill + Northwestern + Cornell
Background: All the processes leading to neurodegeneration cannot be addressed with just one medication. Combinations of drugs affecting various disease mechanisms concurrently could demonstrate improved effect in slowing the course of Parkinson’s disease (PD).
Objective: This was a drug-repurposing experiment designed to assess several combinations of nine drugs for possible added or synergistic efficacy using in vitro models of PD.
Methods: We evaluated 44 combinations of the nine medications (sodium phenylbutyrate, terazosin, exenatide, ambroxol, deferiprone, coenzyme-Q10, creatine, dasatinib and tauroursodeoxycholic acid) selected for their previously demonstrated evidence of their impact on different targets, showing neuroprotective properties in preclinical models of PD. We utilized wild-type induced pluripotent stem-cell-derived human dopaminergic neurons treated with 1-methyl-4-phenylpyridinium for initial screening. We retested some combinations using an idiopathic PD patient-derived induced pluripotent stem cell line and alpha-synuclein triplication line. We assessed anti-neuroinflammatory effects using human microglia cells. As metrics, we evaluated neurite length, number of branch points per mm2, the number of live neurons, neurofilament heavy chain and pro-inflammatory cytokines.
Results: We have identified four combinations of two to three drugs that showed an additive protective effect in some endpoints. Only the combination of sodium phenylbutyrate, exenatide and tauroursodeoxycholic acid showed improvement in four endpoints studied.
Conclusions: We demonstrated that some of the medications, used in combination, can exert an additive neuroprotective effect in preclinical models of PD that is superior to that of each of the compounds individually. This project can lead to the development of the first treatment for PD that can slow or prevent its progression.
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Its all a question as to at what point you catch the process that causes PD.
Regarding this great paper: what happens first, DNA damage or alpha-syn aggregation?
Melatonin is interesting as it might protect from DNA damage and/or improve DNA damage repair capacity: Melatonin megadoses? - #295 by adssx
And there’s some evidence in PD: Parkinson's disease - #679 by adssx
Also:
- α-Synuclein reduces acetylserotonin O-methyltransferase mediated melatonin biosynthesis by microtubule-associated protein 1 light chain 3 beta-related degradation pathway 2024: “Our findings showed that α-SYN reduced the level and activity of melatonin synthesis enzyme acetylserotonin O-methyltransferase (ASMT) in the pineal gland and in the cell cultures. In addition, we found that microtubule-associated protein 1 light chain 3 beta (LC3B) as an important autophagy adapter is involved in the degradation of ASMT. […] One possible reason of this mitigative effect is that injection of melatonin reduces the toxic α-SYN in the important RBD brain tissues. We detected the melatonin level and the α-SYN level in the circadian clock regulation center (hypothalamus), the results showed that melatonin is decreased in the hypothalamus of TG mice, which can be increased after injection of melatonin. While the protein level of α-SYN is nearly unchanged before or after injection of melatonin. These results tend to that the changed RBD-like behaviors in TG mice after melatonin injection are a result from a rescuing effect of melatonin. However, these results in other important RBD brain tissues remain to be further explored. […] Although melatonin affects the α-SYN induced RBD-like behaviors, the photo-instability of melatonin determines its limitations in the induction of these behaviors, indicating that there may be other important molecules in the process. For instance, the hypocretin neurons control motor during wakefulness and sleep in humans, their deficiency induces a motor control defect during REM sleep”
- Melatonin MT1 receptors regulate the Sirt1/Nrf2/Ho-1/Gpx4 pathway to prevent α-synuclein-induced ferroptosis in Parkinson’s disease 2024: “Our findings reveal a novel mechanism by which MT1 activation prevents α-syn-induced ferroptosis in PD, highlighting the neuroprotective role of MT1 in PD.”
- Microglial Melatonin Receptor 1 Degrades Pathological Alpha-Synuclein Through Activating LC3-Associated Phagocytosis In Vitro 2024: “Taken together, the results suggest the neuroprotective function of microglial cells in clearing α-Syn through MT1-mediated LAP, highlighting the potential key role of MT1 in pathogenic mechanisms associated with α-Syn.”
- Modulation of autophagy by melatonin and its receptors: implications in brain disorders 2024
- Effect of melatonin on α-synuclein self-assembly and cytotoxicity 2012: “Initial studies revealed that Mel blocked αS fibril formation as well as destabilizing preformed αS fibrils. Subsequent evaluation of the assembly-stage specificity of the effect showed that Mel was able to inhibit protofibril formation, oligomerization, and secondary structure transitions. Importantly, Mel decreased αS-induced cytotoxicity. These data suggest a mechanism of action for Mel, inhibition of assembly of toxic polymers and protection of neurons from their effect.”
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Doctor Behind Award-Winning Parkinson’s Research Among Scientists Purged From NIH
“Multiple sources at the NIH, granted anonymity because they were not authorized to talk to the media, confirmed Tuesday afternoon that at least 10 principal investigators who were leading and directing medical research at the agency had been fired. Among them is Dr. Richard Youle, a leading researcher in the field of neurodegenerative disorders previously awarded the Breakthrough Prize in Life Sciences for his groundbreaking research identifying mechanisms behind Parkinson’s disease.”
Given how long it takes to establish research infrastructure, this development is not good. Even if these scientists get work at other institutions immediately, it takes time to set up new studies, set goals, get the necessary collaborators and so on.
And getting fired means that whatever research program they were in the middle of, is now disrupted or collapsed.
Neurodegenerative disease studies take a long time. It is unfortunate that a lot will now be set back. Rates of PD are increasing and we need to tackle this as soon as possible.
I am very sad and disappointed with these developments. I always thought of medical research as a steadily growing endeavor. I didn’t expect that as the 21st century is progressing, we’ll actually retrench our efforts, just as the needs of an aging population grow. Pretty discouraging. I don’t understand it - we’re all in this together, including those who have made these decisions, medical science affects their and their families lives too. Who thinks, “whelp, I and my family don’t need medical science, we’re good.” SMH.
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Sometimes you have to wonder what some people are thinking.
Personally, I think those people aren’t thinking at all.
This is a horrible loss to humanity.
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Targeting mitochondria-regulated ferroptosis: A new frontier in Parkinson’s Disease therapy 2025
Mitochondrial dysfunction is a key driver of ferroptosis in PD.
Altered mitochondrial function affects ETC, TCA, and mLIP to promote ferroptosis.
Ameliorating mitochondrial damage-induced ferroptosis holds a great promise for the therapeutic approach for PD
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I intend writing up a post about melatonin and the levels required to protect neurons some time today.
I have started writing this up, but I think it will take a few days to bring together all the separate research.
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Not sure if this is relevant to Parkinson’s specifically:
Intermittent fasting and neurocognitive disorders: What the evidence shows
Conclusion: Current findings highlight the therapeutic potential of IF for individuals with existing cognitive impairment. While preclinical studies provide robust evidence of neuroprotective mechanisms, human studies remain sparse and require standardization. Further clinical research is necessary to confirm long-term safety and efficacy and to refine IF protocols for broader clinical application.
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