#612

Leukocytes are not brain cells.

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#613

OK so not the sentence itself but the LLM’s line of reasoning.

FYI Indian article from last year: Melatonin-Loaded Nanoparticles Augment Mitophagy to Retard Parkinson’s Disease

#614

I am happy to go through all of it line by line, but this particular line was clearly wrong. Reviewing the paragraph has no particular semantic value.

I don’t think melatonin has to be in any nanoparticles, chewing it and taking it sublingually is not bad.

Where I am not sure is whether there is actual benefit beyond preventing mtDNA mutations. There may be, and I would be pleased if there is, but I am not sure.

#615

Is there an indication that there is a structural difference in mtDNA between mitochondria in nerve cells and mtDNA from fibroblasts, or other cell types in the same individual in “healthy” individuals.

If not then the question arises would it be possible to isolate mitochondria from other easy accessible tissue and get them into the brain of persons with parkinson, alzheimer, ALS etc.
Or could these easy accessible tissues from diseased persons be used to study safety and therapeutic effectiveness of possible interventions?

#616

Various research groups are looking at mitochondrial transplant

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#618

I asked the new GPT-4.5 (with Deep research) to analyze and challenge the hypothesis again. It’s at the end here: ChatGPT - Parkinson's Disease Causes Analysis

A few interesting points:

Significant potential of melatonin therapy in Parkinson’s disease – a meta-analysis of randomized controlled trials 2023

Melatonin ≥10 mg/day for a minimum duration of ≥12 weeks in immediate-release formulations consistently demonstrated significant therapeutic potential in improving motor symptom and sleep disturbances in Parkinson disease. However, further trials are warranted to investigate its impact when initiated early in the disease course to fully explore its true therapeutic potential.

However, it’s a Pakistani review, published in Frontiers. And it’s only based on small low-quality trials. The two with higher melatonin doses are from Iran (n=60, 10 mg) and Mexico (n=13, 50 mg)…

Quotes from GPT-4.5:

  • “Overall, many PD patients exhibit circadian rhythm disturbances and poor sleep, consistent with melatonin dysregulation, but whether this is a cause of neurodegeneration or a result of it remains unclear. […] In summary: PD pathology definitely involves mitochondrial dysfunction – a point strongly aligning with Hemming – but whether low melatonin is the trigger for that dysfunction is not definitively proven.”
  • “This suggests a complementary angle: individuals with robust melatonin levels might be more resistant to environmental oxidative insults, whereas those with low melatonin (e.g. due to aging or circadian disruption) could be more susceptible. Hemming’s theory could thus mesh with environmental explanations by positioning melatonin as a moderator of toxin-induced damage. Still, the existence of toxin-induced PD cases shows PD can arise even if melatonin production was normal before exposure.”
  • “According to Braak’s hypothesis, an environmental pathogen or toxin enters through the GI tract or nose and triggers misfolding of α-synuclein in the enteric or peripheral nervous system​. This rogue α-synuclein then travels via the vagus nerve or olfactory pathways to the brain, spreading the disease upward in a predictable pattern. Supporting this, many PD patients have early non-motor symptoms like constipation, loss of smell, and REM sleep behavior disorder long before tremors or movement issues. Gastrointestinal biopsies in high-risk individuals (and animal studies) have shown α-synuclein accumulation in the gut. Furthermore, cutting the vagus nerve in humans has been associated with lower PD incidence, suggesting an interrupted gut-brain route can be protective. Implications: If PD often begins in the gut, melatonin’s role would be peripheral in those early stages. The gut does produce some melatonin locally (in enterochromaffin cells), but its relation to PD pathology is not well understood. Hemming’s hypothesis focuses on the brain aging aspect, whereas the gut-brain model emphasizes a peripheral trigger. They aren’t directly contradictory – one could imagine a scenario where a gut-born α-synuclein pathology eventually causes inflammation and stress in the brain, and if that brain is also melatonin-deficient, the stage is set for faster neurodegeneration. Nevertheless, the gut-brain theory highlights that PD may originate from factors completely unrelated to the pineal/melatonin system (like gut microbiota, pathogens, or environmental chemicals in food). It’s a reminder that PD is systemic, involving multiple organs and mechanisms”
  • “Idiopathic PD classically presents with very specific motor symptoms (resting tremor, rigidity, bradykinesia) that often begin asymmetrically – for example, a unilateral hand tremor is a common first sign​. This focal onset and side-to-side asymmetry don’t intuitively fit a global melatonin deficiency (which would presumably affect the whole brain evenly). If reduced melatonin caused generalized brain aging, one might expect more symmetric, diffuse impairment rather than one side of the body showing symptoms years before the other. Additionally, many non-motor symptoms (loss of smell, constipation, REM sleep behavior disorder, depression) appear in PD patients years before classic motor deficits​. This prodromal phase suggests a specific pattern of early neuronal dysfunction (e.g. in olfactory pathways or the brainstem) that a melatonin-centric framework struggles to explain – melatonin loss would be a broad systemic change, not targeted to, say, the olfactory bulb or gut nerves in the early years of PD.”
  • “The melatonin/aging hypothesis doesn’t provide a clear reason why one person’s “accelerated aging” would manifest mainly as tremor with slow progression, while another’s would manifest as rapid gait disorder and cognitive decline. In other words, a single-factor cause (melatonin deficiency) has trouble accounting for the different clinical phenotypes of PD.”
  • “Notably, one would expect that people with chronically low melatonin (e.g. due to shift work or insomnia) might be at higher risk of PD, yet large studies have not found a clear link – long-term night shift workers, for example, did not show higher PD incidence (one study even found lower PD rates among those with 15+ years of night shifts)​, which is hard to reconcile with a pure melatonin-deficiency theory.”
  • “Melatonin is a potent antioxidant and might protect mitochondrial DNA, but there’s no clear reason why melatonin deficiency would cause α-synuclein to misfold and clump into Lewy bodies. Lewy pathology hints at specific molecular processes (protein misfolding and aggregation) that go beyond generalized oxidative damage.”
  • “Different from Normal Aging: Aging does cause some loss of neurons (including dopamine neurons) and accumulated oxidative stress, but it’s relatively modest. For example, studies estimate that humans lose ~7% of substantia nigra dopamine neurons per decade as part of normal aging – not insignificant, but far too slow to cause Parkinsonian symptoms in a normal lifespan​. More importantly, the pattern of cell loss in PD is distinct from aging. Research indicates that in normal aging, any dopamine neuron loss may affect different subpopulations than those devastated in PD​. PD tends to wipe out the ventral tier of the substantia nigra neurons to a much greater degree, whereas aging has a more diffuse or dorsal pattern of loss”
  • “Braak’s hypothesis suggests that in many cases, PD pathology begins in the olfactory system or the gut (enteric nervous system) years before it reaches the substantia nigra​. The observation that many patients have anosmia (loss of smell) and constipation long before motor symptoms supports this. According to this hypothesis, a pathogen or environmental trigger might initiate misfolding of α-synuclein in the nose or gut, which then propagates upward via neural connections, eventually depositing Lewy bodies in the brainstem and midbrain​. A melatonin-centered hypothesis doesn’t easily account for this “bottom-up” spread of PD pathology. Melatonin in CSF primarily bathes the brain; it’s not obvious how a lack of melatonin in CSF would cause protein aggregates to first appear in the gut or peripheral nervous system.”
  • “Many individuals with high pesticide exposure developed PD presumably with normal melatonin levels for their age, because the toxin itself is sufficient to start killing off dopamine neurons. Melatonin might modulate the severity of toxin-induced damage, but it’s not the root cause of why those people got exposed to a neurotoxin. Thus, pesticide-linked PD suggests an etiology outside of aging – it’s more akin to an acquired injury to the nigrostriatal neurons. Any theory of PD causation needs to accommodate the fact that some cases are toxin-induced, and a purely aging/melatonin theory doesn’t unless it incorporates these as separate or synergistic factors.”
  • “Additionally, autopsy studies show Lewy pathology in the enteric nervous system and vagus nerve early in PD. This has led to the idea of “body-first” or “gut-first” PD, where the disease process might be triggered in the periphery (possibly by environmental factors like pathogens or gut dysbiosis) and later reaches the brain. Hemming’s hypothesis, focused on CSF melatonin and brain aging, doesn’t have an obvious role for the gut. Melatonin is produced in the gut as well (the GI tract actually contains substantial melatonin, but it primarily acts locally in the gut and doesn’t follow the circadian rhythm of pineal melatonin)”
  • “current smokers have about a 60% reduced risk of PD compared to non-smokers, according to pooled data […] From the perspective of melatonin deficiency: smoking is actually known to suppress melatonin secretion (nicotine and the lifestyle of smoking can disrupt normal sleep/wake patterns). If anything, smokers might have lower melatonin levels than comparable nonsmokers. Yet they get PD less often, which flat-out contradicts the expectation that less melatonin equals more PD. The melatonin hypothesis doesn’t readily account for the protective effect of smoking and caffeine – one would have to invoke completely different mechanisms (nicotine’s effect on dopamine neurons or anti-inflammatory properties, caffeine’s adenosine receptor antagonism, etc.). This again shows that PD risk is modulated by a web of factors.”
  • “Despite the lack of overt anatomical damage in most cases, TBI is known to alter melatonin secretion, implying functional pineal impairment. Clinical studies show that patients with TBI often have reduced nocturnal melatonin levels and disrupted circadian rhythms. For example, TBI survivors (~14 months post-injury) exhibited significantly lower evening melatonin production compared to healthy controls”
  • “Hemming’s hypothesis is quite integrative and novel, so it inevitably highlights some gaps in current knowledge. One major gap is the specific anatomical link – we lack neuroimaging or pathology studies showing pineal recess scarring or melatonin pathway damage in people who later developed PD. Another gap is proving causality: while melatonin levels and mitochondrial health correlate with PD, it’s hard to prove that melatonin loss initiates the disease process as opposed to being a concomitant effect. Additionally, PD pathology involves protein aggregation (α-synuclein) which Hemming’s hypothesis touches only indirectly (via splicing and perhaps acetylation affecting protein homeostasis). There is room to explore how melatonin or trauma might influence α-synuclein aggregation – an area not fully addressed yet.”
  • “There is no finding that outright contradicts the hypothesis, but the evidence is often circumstantial or inferred rather than direct. The hypothesis brings together disparate findings into a coherent story, which is its strength, but it awaits direct validation. Future studies could close these gaps by examining TBI patients’ CSF melatonin levels longitudinally and tracking PD biomarkers, or by experimentally modeling pineal injury in animals to see if Parkinson-like neurodegeneration follows. Until then, Hemming’s idea remains a compelling framework that is partially backed by known science (especially regarding melatonin’s protective role) but not yet an established fact. It emphasizes a potentially crucial insight – that protecting or restoring the brain’s melatonin supply (and circadian health) might be an undervalued strategy in reducing PD risk, particularly in those with head trauma history”
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#619

Also just published: Early detection of Parkinson’s disease through multiplex blood and urine biomarkers prior to clinical diagnosis 2025

Blood and urine biomarkers are commonly used to diagnose and monitor chronic diseases. We initially screened 67 biomarkers, including 4 urine biomarkers and 63 blood biomarkers, and identified 13 blood biomarkers significantly associated with Parkinson’s disease (PD). Among these, we discovered three novel markers demonstrating strong associations: phosphate (P = 1.81 × 10−3), AST/ALT ratio (P = 8.53 × 10−6), and immature reticulocyte fraction (IRF) (P = 3.49 × 10−20). We also substantiated eight well-studied biomarkers and elucidated the roles of two previously ambiguous biomarkers. Our analyses confirmed IGF-1 (P = 7.46 × 10−29) as a risk factor, and C-reactive protein (CRP) (P = 1.43 × 10−3) as protective against PD. Genetic analysis highlighted that IRF, CRP, and IGF-1 share significant genetic loci with PD, notably at MAPT, SETD1A, HLA-DRB1, and HLA-DQA1. Furthermore, Mendelian randomization (MR) analysis suggested potential causal associations between IGF-1, CRP, and PD. We identified several blood biomarkers that may be associated with the risk of developing PD, providing valuable insights for further exploration of PD-related biomarkers.

So hsCRP is protective against PD?!

Genetic correlation analysis revealed significant inverse genome-wide correlations between PD and several biomarkers like eosinophil count, IRF, CRP, glucose, and total bilirubin, while showing a positive correlation with IGF-1. Among these, the relationships with IGF-1 and CRP were the most pronounced.
The genes HLA-DRB1 and HLA-DQA1, which are shared among IGF-1, CRP, and PD, are implicated in immune regulation. These findings suggest a significant role of these genetic regions in modulating immune responses, which may influence the pathogenesis of PD.
Our findings indicate that elevated levels of IGF-1 are associated with an increased risk of PD, while higher baseline levels of CRP are linked to a reduced risk of PD. This study represents the first demonstration of a causal relationship between IGF-1 and PD using MR analysis. These findings enhance our understanding of the association between these two biomarkers and PD risk, providing partial evidence for further exploration of their underlying pathogenesis.
These biomarkers encompass categories such as enzymes, blood cell parameters, metabolites, and proteins. Among these, the AST/ALT ratio (HR = 1.14, 95% CI: 1.08–1.21, P = 8.53 × 10−6), NLR (HR = 1.14, 95% CI: 1.08–1.19, P = 6.06 × 10−7), glucose (HR = 1.13, 95% CI: 1.07–1.19, P = 5.02 × 10−6), IGF-1 (HR = 1.25, 95% CI: 1.20–1.30, P = 7.46 × 10−29), phosphate (HR = 1.08, 95% CI: 1.03–1.12, P = 1.81 × 10−3), and total bilirubin (HR = 1.06, 95% CI: 1.02–1.11, P = 5.31 × 10−3) were positively associated with PD risk. Conversely, platelet crit (HR = 0.76, 95% CI: 0.70–0.83, P = 5.97 × 10−9), eosinophil count (HR = 0.92, 95% CI: 0.88–0.96, P = 4.79 × 10−4), C-reactive protein (CRP) (HR = 0.89, 95% CI: 0.83–0.95, P = 1.43 × 10−3), urate (HR = 0.85, 95% CI: 0.81–0.89, P = 1.13 × 10−10), immature reticulocyte fraction (IRF) (HR = 0.75, 95% CI: 0.71–0.79, P = 3.49 × 10−20), basophil count (HR = 1.31, 95% CI: 1.25–1.37, P = 2.98 × 10−31), and platelet count (HR = 1.10, 95% CI: 1.01–1.20, P = 3.91 × 10−2) were significantly associated with PD risk.
Finally, we conducted stratified analyses by sex and age. In males, NLR, glucose, phosphate, and total bilirubin were no longer significant, while in females, there were no differences (See Supplementary Table 1). In the age-stratified analysis, CRP and phosphate were no longer significant in individuals older than 65 years. After excluding individuals who developed diseases within three years from the baseline measurement, the results remained unchanged, confirming the reliability and stability of our findings. (See Supplementary Table 2).

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#620

I think the flow of CSF through the brain needs to be considered. That is the route through which the higher doses of melatonin are provided to brain cells.

#621

A basic question to ChatGPT (not the advanced type) remembering that aberrant splicing occurs as a result of acetyl-CoA shortage.

does aberrant splicing cause α-synuclein aggregation

ChatGPT said:

Yes, aberrant splicing can contribute to α-synuclein aggregation by altering the expression, structure, and function of α-synuclein itself, as well as other proteins involved in its regulation. Here’s how:

1. Aberrant Splicing of the SNCA Gene (α-Synuclein)

  • The SNCA gene, which encodes α-synuclein, undergoes alternative splicing, producing different isoforms.
  • Some splicing variants may be more prone to aggregation than others.
  • For example:
    • SNCA-115 and SNCA-98 are shorter isoforms that may disrupt normal α-synuclein function.
    • Dysregulation of exon skipping or alternative exon inclusion could favor the production of aggregation-prone forms.

2. Disruptions in Splicing Factors Affecting α-Synuclein Aggregation

  • Several splicing factors regulate α-synuclein expression and processing.
  • If these factors are misregulated or sequestered into α-synuclein aggregates, it creates a vicious cycle that promotes further aggregation.
  • Example: SRSF1 (Serine/Arginine-Rich Splicing Factor 1) has been shown to regulate SNCA splicing. Its dysfunction may lead to increased aggregation-prone α-synuclein isoforms.

3. Splicing Errors in Genes That Regulate α-Synuclein Clearance

Aberrant splicing can also affect genes responsible for degrading or preventing α-synuclein aggregation, such as:

  • LRRK2 (Leucine-rich repeat kinase 2): Mutations and splicing defects can impair autophagy, leading to α-synuclein buildup.
  • Parkin (PARK2): Splicing errors in Parkin reduce its ability to clear aggregated proteins.
  • DJ-1 (PARK7): Mis-splicing can make neurons more vulnerable to oxidative stress, indirectly promoting aggregation.

4. RNA Dysregulation and Toxic Protein Accumulation

  • α-Synuclein interacts with RNA-binding proteins involved in splicing, and when these are disrupted, it can lead to toxic protein accumulation.
  • For example, TDP-43, a well-known RNA-binding protein, has been implicated in both α-synucleinopathies and ALS.

Conclusion: A Vicious Cycle

  1. Aberrant splicing → Increased aggregation-prone α-synuclein isoforms.
  2. Splicing factor dysfunction → Impaired degradation of α-synuclein.
  3. α-Synuclein aggregates → Sequestration of splicing factors, worsening splicing errors.

This creates a self-reinforcing loop where splicing defects accelerate α-synuclein aggregation, driving neurodegeneration.

Would you like details on specific studies or mechanisms?

#622

I think there are some clues in circadian rhythm disruptions in PD subjects. I am skeptical of insufficient melatonin being causal, because melatonin inhibits central dopamine secretion. For example administering exogenous melatonin worsens RLS symptoms, and conversely, inhibiting melatonin with a strong light ameliorates RLS symptoms.

Effects of melatonin and bright light administration on motor and sensory symptoms of RLS

Melatonin in PD dopamine interaction:

Melatonin-dopamine interactions: from basic neurochemistry to a clinical setting

“In Parkinson patients melatonin may, on the one hand, exacerbate symptoms (because of its putative interference with dopamine release) and, on the other, protect against neurodegeneration (by virtue of its antioxidant properties and its effects on mitochondrial activity).”

Circadian rhythm of restless legs syndrome: relationship with biological markers

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#623

Melatonin is complex as it has effects on a number of levels.

I think the timing of melatonin release/dosing is very important.

However, the body creates melatonin to protect particularly mitochondrial DNA.

1 Like
#624

Oops, I forgot to include the circadian rhythm PD paper in my previous post.

Circadian rhythms, Neuroinflammation and Oxidative Stress in the Story of Parkinson’s Disease

#625

Same question, answer by Chat GPT-4.5 Deep research: ChatGPT - Aberrant Splicing in PD

#626

NIH preprint just published: Novel reporter of the PINK1-Parkin mitophagy pathway identifies its damage sensor in the import gate 2025

Damaged mitochondria can be cleared from the cell by mitophagy, using a pathway formed by the recessive Parkinson’s disease genes PINK1 and Parkin. How mitochondrial damage is sensed by the PINK1-Parkin pathway, however, remains uncertain. Here, using a Parkin substrate-based reporter in genome-wide screens, we identified that diverse forms of mitochondrial damage converge on loss of mitochondrial membrane potential (MMP) to activate PINK1. Consistently, the MMP but not the presequence translocase-associated motor (PAM) import motor provided the essential driving force for endogenous PINK1 import through the inner membrane translocase TIM23. In the absence of TIM23, PINK1 arrested in the translocase of the outer membrane (TOM) during import. The energy-state outside of the mitochondria further modulated the pathway by controlling the rate of new PINK1 synthesis. Our results identify separation of PINK1 from TOM by the MMP, as the key damage-sensing switch in the PINK1-Parkin mitophagy pathway.
Highlights

  • MFN2-Halo is a quantitative single-cell reporter of PINK1-Parkin activation.
  • Diverse forms of mitochondrial damage, identified in whole-genome screens, activate the PINK1-Parkin pathway by disrupting the mitochondrial membrane potential (MMP).
  • The primary driving force for endogenous PINK1 import through the TIM23 translocase is the MMP with the PAM import motor playing a supporting role.
  • Loss of TIM23 is sufficient to stabilize PINK1 in the TOM complex and activate Parkin.

Importantly, the proposed model also points to how the PINK1-Parkin pathway may be pharmacologically tuned to promote clearance of damaged mitochondria in disorders caused by mitochondrial damage. Small molecules that upregulate glycolysis, such as the PGK1 activator terazosin, may help support PINK1-Parkin surveillance of mitochondrial damage, by providing ATP needed for new PINK1 synthesis and PINK1-Parkin activation. This may be particularly critical in sporadic Parkinson’s disease, where energy deficiency is likely present in the affected dopamine neurons. Additionally, the MMP threshold of PINK1-Parkin activation may be lowered by decreasing mitochondrial ATP levels. This may have an effect that is similar to MTK458, a PINK1 activator under development by Mitokinin/AbbVie, which was shown to lower the CCCP dose required for PINK1-Parkin activation, similar to the effect of oligomycin observed here. Conversely, small molecules that stabilize the binding site for PINK1 in the TOM complex, buttressed by TOMM5 and TOMM7, may allow PINK1 stabilization at a higher MMP. Either strategy – strengthening PINK1 binding to the TOM translocase or lowering the driving force through the TIM23 translocase – would have a similar effect: increasing the sensitivity of the PINK1-Parkin mitophagy pathway for damaged mitochondria. Finally, we anticipate the MFN2-Halo reporter will help aid drug discovery, as a quantitative, single-cell reporter that is orthogonal to the widely used mitophagy-based reporters.

#627

Parkinson's disease - #618 by adssx by @adssx states “cutting the n. vagus … protects against PD”

my take:

  1. one of the early symptoms is constipation
  2. anticholinergic drugs often cause constipation this seems contradictory
    The MAYOR question however may be : can anticholinergic drugs not only treat some symptoms but also prevent progression of early disease.
#628

They’ve been used for a long time in PD and don’t seem to have any neuroprotective effect.

1 Like
#629

Press: Men’s immune response to brain protein may explain their higher rates of Parkinson’s disease 2025

In recent years, LJI scientists have found increasing evidence that autoimmunity plays a role in the onset of Parkinson’s disease. Their recent study in the Journal of Clinical Investigation shows that PINK1 appears to mark some brain cells for immune cell attack.
PINK1 means no harm. The protein actually helps brain cells regulate their mitochondria—the cellular structures that provide energy for a cell. The researchers found that some people with Parkinson’s disease have T cells that mistakenly see PINK1 as a red flag. These T cells may target brain cells that express PINK1, contributing to inflammation and brain cell death.
The new research may help explain why Parkinson’s disease is around twice as common in men as in women. The LJI team found that men with Parkinson’s disease had a six-fold increase in PINK1-specific T cells, compared with healthy male study participants. Women with Parkinson’s disease showed only a 0.7-fold increase in PINK1-specific T cells, compared with healthy female study participants.

Paper: PINK1 is a target of T cell responses in Parkinson’s disease 2024

Within the brain, activation of resident microglia and astrocytes leads to the expression of proinflammatory cytokines, directly inducing neurotoxicity and recruiting immune cells, such as T cells, from the periphery.
T cell reactivity in PD is not associated with early time points or other clinical characteristics.
Not all patients with PD have α-syn–specific T cell reactivity (15, 16). To determine whether patients with PINK1-specific T cells also have α-syn–specific T cell reactivity, we correlated the total magnitude of reactivity against PINK1 with the total magnitude against α-syn (n = 53 participants that responded to either PINK1 or α-syn, Supplemental Figure 3). There was no correlation between reactivity for the 2 proteins and no significant overlap in response to both antigens (2-tailed Fisher’s exact test, P = 0.168).
Our previous work (15, 16) and the work of others (17, 45) have shown that α-syn is a target of peripheral T cell responses in some PD patients. However, not all PD patients possess these autoinflammatory T cells, and for those who do, their frequency wanes over the course of the disease (15). We have also previously shown that τ is recognized by T cells broadly in the population irrespective of age and disease status (39).
In conclusion, our study has identified PINK1 as a common autoantigenic target of T cells in PD. These responses are predominantly associated with male PD individuals, multiple secreted cytokines toward PINK1 were observed, and specific epitopes and corresponding restricting HLA alleles are reported. These results reinforce the need for studying PD in the context of the immune system, with the goal of developing personalized immune-based therapies.

Can’t wait for the azathioprine trial results!

#630

A sub-study of azathioprine in Parkinson’s 2022

This will provide information on whether azathioprine is able to ‘correct’ the Parkinson’s immune profile and reduce inflammatory immune cells entering the brain, which will indicate whether it should be further tested as a future Parkinson’s treatment.
Dr.Williams-Gray – “This trial will allow us to test a brand new strategy of suppressing the immune response to slow the progression of Parkinson’s disease. Our primary measure of the efficacy of azathioprine will be how it affects movement and balance. But in addition to testing whether the drug has a clinical benefit, we want to understand precisely how it is altering the immune system in Parkinson’s. This additional funding from Cure Parkinson’s will allow us to investigate this in both the blood and cerebrospinal fluid – the fluid that bathes the brain. We already know that immune cells cross from the blood into the brain in Parkinson’s and we think this might be important in driving faster disease progression. The key question that this sub-study will address is whether azathioprine treatment can reduce the entry of these cells into the brain – so helping us to understand how the drug might have an effect on this disease.”

@John_Hemming @DrFraser: if correct, this might explain the potential benefits of sirolimus (via immunosuppression rather than mTOR inhibition) in PD despite no brain penetrance. (At least early in the disease?)

[EDIT: results of that trial expected in the next few weeks]

#631

If Parkinsons is primarily an autoimmune disease. The fact that there may be autoimmunity in the process does not, however, mean it is upstream. Hence there could be some symptomatic benefit from that. It is good to relieve symptoms, but the cause needs to be clarified to make the most progress.

2 Likes
#632

ChatGPT 4.5 says:

If the hypothesis regarding rapamycin’s peripheral immunomodulation (particularly suppression of harmful T-cell responses, such as those targeting PINK1) is correct, it would have profound implications for its potential use in Parkinson’s disease (PD):

1. Symptomatic Relief vs. Disease Modification

  • Symptomatic relief means managing symptoms without altering the underlying disease mechanisms.
  • Disease modification refers to interventions that actually slow or halt disease progression by addressing fundamental pathogenic mechanisms.

In this scenario, rapamycin would primarily function as a disease-modifying therapy rather than merely providing symptomatic relief. Here’s why:

  • If immune activation (e.g., T-cell responses against PINK1) contributes directly to neuronal injury or neurodegeneration, suppressing this mechanism would likely reduce ongoing neuronal damage, not just mask symptoms.
  • Rapamycin’s immunosuppressive effects, therefore, might slow or even halt the progression of neuronal loss by preventing further immune-mediated harm.

2. Preventive Use (Before Diagnosis)

Rapamycin would likely be highly beneficial as a preventive strategy, especially for high-risk populations (e.g., those with family history, genetic predispositions, or identified elevated immune responses such as high PINK1-specific T cells):

  • Prophylactic intervention could significantly reduce or delay the onset of PD by suppressing harmful T-cell-mediated inflammation before substantial neuronal damage occurs.
  • Earlier intervention could prevent the cascade of inflammation and neurodegeneration altogether or substantially delay its initiation.

3. Use After Diagnosis

Rapamycin could also potentially provide significant benefits after diagnosis, although the magnitude and nature of these benefits would depend on timing:

  • Early-stage patients might experience substantial disease-modifying effects if initiated soon after diagnosis, preserving neurons and function.
  • In advanced stages, effectiveness may be more limited, given that significant neuronal loss has already occurred. Still, immunomodulation could prevent further progression or protect remaining neuronal populations.

4. Practical Implications and Considerations

  • Combination therapy: Rapamycin might be most effective when combined with other disease-modifying or symptomatic treatments (dopaminergic therapies, neuroprotectants, or lifestyle interventions).
  • Dosing and timing: Optimal therapeutic windows, dosing schedules (intermittent versus daily), and personalized medicine approaches (tailored immunological biomarkers) would become critical.

Conclusion

If the current immune-driven hypothesis is correct, rapamycin could have a robust disease-modifying (rather than purely symptomatic) role. Its potential effectiveness could span from preventing onset in high-risk individuals to slowing disease progression after diagnosis, especially if initiated early.

Future research should clarify optimal timing, dose regimens, and patient populations that will benefit most significantly from such immunomodulatory strategies.

I think it’s smart. Hopefully we’ll soon know more with the azathioprine trial results. I hope they’ll stratify the results by gender.

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