Parkinson's disease

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Just published: Sympathetic and parasympathetic subtypes of body-first Lewy body disease observed in postmortem tissue from prediagnostic individuals 2025

3 subtypes of PD:

• Brain-first
• Parasympathetic body-first
• Sympathetic body-first

Not sure your theory can explain these subtypes @John_Hemming.

[John_Hemming]

My hypothesis is based upon the flow of melatonin. Hence looking at proteins does not help. We need to look at the flow of melatonin in the CSF.

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But I don’t see how the flow of melatonin in the CSF could make PD start in the gut or brain and propagate through the sympathetic or parasympathetic nervous system.

[RapAdmin]

Good news for the future of Parkinson’s treatment:

Paywalled paper:

https://www.science.org/doi/10.1126/science.adu6445

[Karel1]

Given the huge body of information in this topic and all references mentioned my request would be a new topic that summarizes early symptoms for the different types of parkinson’s and the interventions that might slow down progression.

If I read the info well some 40-50% of dopaminergic cells may still be available in the brain by the time that a well trained GP may recognize the disease. If it can be halted at that level there may be a great differences in QOL. So it is enormously important to spread this info.

[John_Hemming]

I will need to spend more time reading the paper.

[John_Hemming]

I have had another look at this. I think you are referring to the three subtypes of lewy body disease in extended data fig 3. Those are in different parts of the CNS. All of these are fed via the CSF. It does not flow the same way blood does, but there is still a circadian cycle of melatonin levels with the peak levels in the third ventricle being highest. It also can be blocked

Physiology, Cerebral Spinal Fluid

Hence blockages in different places will have different consequences.

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This might answer your questions: Parkinson's disease - #429 by adssx

[cl-user]

Amazing (paywalled) paper: Structure of human PINK1 at a mitochondrial TOM-VDAC array

The supplementary materials file is not paywalled though.

[John_Hemming]

is pink1 subject to splicing errors

ChatGPT said:

Great question! Yes, PINK1 (PTEN-induced kinase 1) — a gene crucial for mitochondrial quality control — can be subject to splicing errors under certain pathological or stress conditions. Here are some key points about PINK1 and splicing:

1. Normal Splicing of PINK1

• PINK1 encodes a mitochondrial-targeted kinase, and its proper function is essential for mitochondrial health, especially in neurons.
• It has multiple exons and produces different isoforms via alternative splicing, but usually, the full-length PINK1 is the functionally relevant form for mitophagy (recruitment of Parkin to damaged mitochondria).

2. Splicing Errors in PINK1

• Splicing mutations in PINK1 can lead to aberrant transcripts that may be non-functional or degraded by nonsense-mediated decay (NMD).
• Such errors can include:
  • Exon skipping
  • Intron retention
  • Use of cryptic splice sites
• These errors can produce truncated proteins or proteins with altered function, potentially leading to mitochondrial dysfunction.

3. PINK1 Mutations in Disease

• Several familial Parkinson’s disease (PD) cases are linked to mutations that affect PINK1 splicing.
• For instance, intronic mutations near splice donor/acceptor sites can disrupt normal splicing.
• Aberrant splicing variants have been reported in PINK1-linked early-onset Parkinson’s disease (EOPD).

4. Experimental Evidence of Splicing Variants

• Studies have shown alternative splicing of PINK1 mRNA, and some of these isoforms may lack mitochondrial targeting sequences, preventing normal localization and function.
• Certain environmental stresses or mutations can shift splicing patterns toward non-functional forms.

---

Summary

• Yes, PINK1 is subject to splicing errors, especially in the context of genetic mutations or potentially under stress.
• These errors can contribute to mitochondrial dysfunction and neurodegeneration, such as in Parkinson’s disease.
• Understanding PINK1 splicing is an active area of research for developing therapeutics targeting mitophagy pathways.

If you want, I can pull up specific examples of known PINK1 splicing mutations in Parkinson’s. Would you like that?

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Intranasal administration of isradipine preferentially targets the brain 2025

Preprint

Parkinson’s disease (PD) is the second most common neurodegenerative disease. Despite a concerted effort on the part of the scientific community, there is no proven strategy for slowing PD progression. Nevertheless, there are several potential drug targets that if functionally modified could alter disease course. Preclinical, epidemiological and clinical trial data suggest that Cav1 Ca2+ channels are one such target. Dihydropyridines (DHPs) are voltage-dependent, negative allosteric modulators of Cav1 Ca2+ channels that are approved for human use. However, the brain concentration of DHPs that can be safely achieved in humans with oral dosing is limited because of the widespread distribution of these channels, particularly in the vasculature. Intranasal administration of DHPs is a potential alternative delivery strategy that has been used with compounds that have similar limitations. To test the viability of this drug administration strategy, mice were intranasally or orally administered the DHP isradipine mixed in one of three vehicles. Plasma and brain concentrations of isradipine were then determined using liquid chromatography/mass spectroscopy at subsequent times. These studies demonstrated that intranasal administration of isradipine was able to achieve higher brain concentrations than those in the plasma, and these differences persisted for hours. Thus, intranasal administration of DHPs could be used to achieve high levels of Cav1 Ca2+ channel inhibition in the brain without producing unwanted peripheral side-effects.

(@John_Hemming on the hypothesis:)

One hypothesis about PD pathogenesis is that the loss of at-risk neurons is driven by sustained oxidant stress arising from the reliance upon feed-forward control of mitochondrial oxidative phosphorylation 3. Key nodes in this control network are plasma membrane, voltage-dependent Ca2+ channels with a Cav1 pore-forming subunit 4. Dihydropyridines (DHPs) are negative allosteric modulators of these channels that have been shown to lower mitochondrial oxidant stress in at-risk neurons and to lessen the sensitivity to toxins and genetic mutations associated with PD. Moreover, epidemiological studies have consistently found that use of DHPs is associated with a reduced risk of developing PD 5,6,7,8,9. These observations led to a Phase 2 clinical trial that found at the maximum tolerated dose of a controlled release format of the DHP isradipine (10 mg/day), disease progression measured through clinical evaluation significantly slowed 10. However, a Phase 3 study using a similar daily dose of an immediate release (IR) format of isradipine failed to hit its clinical endpoints 11 . That said, in patients that cleared IR isradipine more slowly, there were clear signs of disease slowing 12 .
In the last series of experiments, intranasal administration of isradipine was compared to oral gavage. With DMSO as the vehicle for isradipine, oral gavage was much less effective in elevating brain concentrations – even though the brain/plasma ratio remained greater than 1. Unexpectedly, with the N,N-dimethylformamide/PEG400/saline vehicle oral gavage was more effective in elevating brain isradipine concentration than intranasal administration. It is unclear why this was the case. Interestingly, even in this situation, brain concentrations of isradipine were higher than those in the plasma.
In principle, intranasal administration of isradipine could be used to achieve brain concentrations in the protective range (10-20 nM), while keeping plasma concentrations below the threshold for significant side-effects. However, given that isradipine is eventually cleared from the brain, maintaining isradipine within a protective range would require repeated, periodic intranasal dosing. The advent of calibrated, easy-to-use intranasal delivery devices 21 could make this requirement relatively easy to surmount.

[John_Hemming]

This is a question of at what point to try to intervene. The earlier in the process the more effective the intervention.

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Lysophosphatidylcholine promoting α-Synuclein aggregation in Parkinson’s disease: disrupting GCase glycosylation and lysosomal α-Synuclein degradation 2025

During the study, to mitigate the damage caused by LPC, we introduced the small molecule drug solanesol for treatment. The results demonstrated that solanesol significantly ameliorated LPC-induced motor and cognitive dysfunction in mice, reduced α-synuclein (α-Syn) accumulation, and improved LPC-induced lysosomal acidification deficits. These findings suggest that solanesol holds substantial potential as a novel small molecule therapeutic for neurodegenerative diseases. Solanesol, a precursor of Coenzyme Q10, is a potent antioxidant with anti-inflammatory, membrane-stabilizing, antibacterial, and anti-ulcer properties. Coenzyme Q10 has been shown to improve functions in various neurodegenerative diseases, such as PD, amyotrophic lateral sclerosis, Alzheimer’s disease, and multiple sclerosis. It primarily prevents intracellular lipid peroxidation and participates in intracellular signaling. Additionally, Coenzyme Q10 can partially prevent ERK content alterations, highlighting its importance in cellular metabolism84. In our experiment, we observed that LPC-induced ERK phosphorylation via GPR35, and solanesol treatment reduced p-ERK levels, thereby mitigating LPC-induced damage. It should be noted that our study was performed in a rodent cell line and rodent animals; future studies may use iPSC-derived dopaminergic neurons to further strengthen our conclusions.

Solanesol

Solanesol is a non-cyclic terpene alcohol that consists of nine isoprene units and mainly accumulates in solanaceous plants such as tobacco, potato, and tomato.

Might explain why smoking is protective from PD?

Fairly expensive: https://www.scientificlabs.co.uk/product/bioreagents/S8754-25MG

[John_Hemming]

Solanesol possesses antimicrobial, anti-tumor, anti-inflammatory, and anti-ulcer activities, and it serves as an important pharmaceutical intermediate for the synthesis of coenzyme Q10, vitamin K2, and N-solanesyl-N ,N ′-bis(3,4-dimethoxybenzyl) ethylenediamine (SDB).[3]

Perhaps K2 is cheaper.

I wonder if the smoking issue is more oxygen related.

Molecular weight 631.1 MK7 molecular weight 649.

I can get 4.5g of MK7 for about the same price as 25mg of Solanesol.

Obviously the isoprene residues in Solanesol allow it to embed in the mitochondrial membrane, but whether it can act as electron transport or first needs converting to CoQ10 or MK-n (where n is from 7-13) I don’t know.

[CronosTempi]

Globally, 25.2 Million Projected to Be Living With Parkinson Disease in 2050

Globally, 25.2 Million Projected to Be Living With Parkinson Disease in 2050...

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The Gut-Brain Axis in Parkinson disease: Emerging Concepts and Therapeutic Implications 2025

Mounting evidence from preclinical, clinical and post-mortem studies suggests that a subgroup of PD patients present with a range of prodromal symptoms (e.g., autonomic dysfunction, rapid eye movement sleep behaviour disorder) which reflect initial accumulation and later spread of pathological α-synuclein rostrally from the gastrointestinal tract (“body-first” PD). Through neural connections along the gut-brain axis, pathological α-synuclein may spread to the brain, producing clinically manifest disease. Recently, two mechanisms involving the gut-brain axis have attracted increasing attention for their role in PD pathogenesis and progression, namely the perturbation of the composition of the microorganisms living in the gut (the gut microbiome), and the dysfunction of enteroendocrine cells.
Treatments targeting the gut-brain axis, especially the gut microbiome and the enteroendocrine cells pathway, could potentially slow disease progression or even prevent disease onset. Among these, pre/probiotics, faecal microbiota transplantation, and glucagon-like peptide-1 receptor agonists, have entered advanced stages of clinical trials in humans and shown potential symptomatic and disease-modifying effects.

In the last 20 years, research into the gut-brain axis has broadened our understanding of the pathogenesis, phenotypic heterogeneity and clinical trajectories of PD. Building upon the seminal Braak hypothesis, current models of PD pathogenesis support the existence of a body-first subtype of PD where pathological changes might originate in the gut years or even decades prior to brain dysfunction. For this subset of individuals, alterations in the gut microbiome composition and dysfunction of EECs might contribute to the initial pathogenic alterations and potentially affect disease progression.
Research into the microbiome-gut-brain axis has paved the way for the identification of novel therapeutic targets, including symptomatic, disease-modifying and prophylactic treatments, in PD. These treatments might be particularly effective in addressing troublesome, non-motor symptoms such as constipation, but evidence from phase III RCTs, with appropriate study design and patient selection, is needed.

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This is huge: Chronobiotic use of melatonin improves DAT-binding in iRBD

Dieter Kunz1, Jan De Zeeuw2, Sophia Stotz1, Michail Plotkin3, Frederik Bes1
1 Charité – Universitätsmedizin Berlin, Institute of Physiology, Berlin, Germany,
2 Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany,
3 Charité – Universitätsmedizin Berlin, Berlin, Germany
Aims: Isolated REM-sleep behavior disorder (iRBD) is recognized as a prodromal state of clinical α-synucleinopathies such as Lewy-body dementia and Parkinson’s disease. A pathophysiologic hallmark of α-synucleinopathies is nigrostriatal dopaminergic impairment, with dopamine-transporter (DaT)-SPECT imaging considered best available prognostic and monitoring marker. DaT-binding is reported to decrease with healthy aging by 4-10% per decade, accelerated to 4-12% per year iRBD patients. We have introduced melatonin as a treatment option for iRBD. Aim of the study was to evaluate effects of melatonin on DaT-SPECT imaging in iRBD patients.
Methods: In a prospective, longitudinal, observational, single-center study we performed at least two DaT-SPECTs in 97 iRBD patients treated with melatonin as a chronobiotic (i.e. administration always- at-the-the-same-clock-time;10-11p.m.-corrected for chronotype); 28 patients were excluded mainly due to change of psychotropic drugs known to influence DaT.
Results: After mean follow-up of 3.6yrs, only 21/69 patients (11 female; mean age 71±6yrs) showed specific binding ratios (SBR) in most affected region (MAR, predominantly right posterior putamen) comparable to usually reported declines with iRBD. In contrast, 7 had declined SBR at a rate comparable to healthy aging, while 41 had actually improved SBR. Improvement after one year (SBR of MAR; F1,31=23.748;p>0.001) and two years was significant (F1,24=4.648;p=0.041). After four years half of the patients showed a higher SBR than baseline (23 vs. 24 patients), though this was not significant. 47/69 of our patients at baseline met established criteria for an advanced state.
Conclusions: To the best of our knowledge, present data give first evidence for a consistent increase in DaT-binding ratios in nigrostriatum over time in a cohort of patients with iRBD. In addition, the previously reported persisting effect of melatonin on RBD symptoms suggest that melatonin, when used as a chronobiotic, may have a disease-modifying effect in prodromal α-synucleinopathies.

It’s a conference poster so not peer-reviewed yet but it’s a very serious research team, it’s a decent size, over a long period of time and it uses an objective biomarker

Their chronobiotic protocol is “2 mg, ≥6 months, always-at-the-same-clock time, 10-11pm, corrected for chronotype”: Treatment of isolated REM sleep behavior disorder using melatonin as a chronobiotic 2021. In this 2021, paper they note:

Patients on concomitant betablocker or antidepressant therapy seemed to respond more slowly at the beginning of melatonin treatment, although they did not differ in general from the no-confounder group. Both antidepressants and betablockers are known to induce secondary RBD as well as to increase RSWA in patients with iRBD. Antidepressants are well known to influence REM sleep, with anticholinergic agents to suppress, but serotoninergic and noradrenergic agents to spoil the quality of REM sleep. As has been known for decades, lipophilic propranolol blocks melatonin secretion from the pineal gland via beta-receptors. The suppression of melatonin with betablockers predominantly affects REM sleep, which can be reversed by exogenous melatonin. Long-term medication with betablockers is likely to have changed melatonin receptor sensitivity, thus delaying response to initial melatonin. The same negative effect could be attributed to recommended increasing dosage of melatonin. Because melatonin influences its own receptor, it is important to have a melatonin-free period over the day. Supraphysiologic melatonin doses, especially in slow metabolizers, prevent the absence of melatonin during the day and could induce insensitivity in melatonin receptors the next evening.
The rationale for this strict schedule is that since our initial pilot studies with RBD patients about 25 years ago, we repeatedly observed that responders and nonresponders were best distinguished by evaluating their sleep hygiene, that is, stable vs. varying bedtimes and times of melatonin intake (summarized in 10, 17). This clinical observation is in agreement with the fact that melatonin is known to feedback on the suprachiasmatic nucleus, the central pacemaker or master-clock. As a consequence, exogenous melatonin should be administered consistently within a rather narrow time span in order to gain optimal effects. Patients are informed that melatonin in RBD rarely exhibits effects during first days of treatment, rather effects occur within the first weeks. Sometimes symptoms even rapidly worsen over the first days, presumably because appointed time of administration induced a transient initial delay or advance of circadian phase. In those patients, in whom melatonin does not show positive effects over the first 3 weeks of treatment, the time of administration is controlled referring to individual chronotype.
The rate of improvement of RBD symptoms with melatonin in previously reported case series varies, and two recent RCTs have shown no effect. Unfortunately, melatonin has been sold worldwide for the past 25 years as a hypnotic to be administered in connection with clock time independent events (eg, “after a meal,” “at bedtime”). Most people who took melatonin—including those in the two recent RCTs with negative results—will therefore not have adhered to a schedule based strictly on clock time. As an example, in our Clinic for Sleep & Chronomedicine, we precisely explain the chronobiotic protocol but even though, still some patients stuck to the aberrant leaflet prescription. Our study indeed demonstrates that beneficial effects of melatonin can easily be disrupted with improper timing of intake, which may well explain lower response rates reported by other groups. In those patients for whom we had a chance to reinstruct, melatonin improved RBD symptoms. On the other hand, melatonin should not be considered a harmless drug or being without side effects. Inadequate timing of melatonin seems likely not only to fail in improvement, but rather to worsen symptomatology due to desynchronization.

What do you think about this potential risk @John_Hemming?

[John_Hemming]

I think a study is needed as to timing of melatonin linked to the timing of the HPA axis.

On the other hand, melatonin should not be considered a harmless drug or being without side effects.

When there have been reports of claimed harm from melatonin I have chased down the case reports and they did not substantiate the claim.

I am not sure the effects in terms of protection of mtDNA are that sensitive to timing, however.

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Selegiline looks good: Anyone taking Selegiline / Deprenyl For Longevity? - #90 by adssx

Regarding the melatonin conference abstract, although they only looked at DAT imaging, they showed in a previous paper that “Most RWA metrics correlated significantly with DAT-SPECT ratios (eg, Montreal tonic vs most-affected-region: r=−0.525; p<0.001).” (Prognostic biomarkers in prodromal α-synucleinopathies: DAT binding and REM sleep without atonia 2023)

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Just published on melatonin @John_Hemming: Clinical features, plasma neurotransmitter levels and plasma neurohormone levels among patients with early-stage Parkinson’s disease with sleep disorders 2025

RBD was associated with dysautonomia and was negatively correlated with the plasma melatonin concentration at 1:00 AM (r = − 0.40, p = 0.002) in early-stage PD patients.
REM sleep behavior disorder (RBD) was linked to dysautonomia and lower levels of melatonin at 1:00 AM, restless legs syndrome (RLS) was associated with poorer sleep quality and lower levels of serotonin and glutamine at different times.
Previous studies have confirmed that the principal neuroendocrine system and the crucial neurotransmitter systems that mediate sleep, including melatonin, acetylcholine, norepinephrine, serotonin, dopamine, and gamma-aminobutyric acid, are disrupted in PD.
In healthy controls, the plasma dopamine level at 1:00 am was significantly lower than that at 9:00 am, and the melatonin level at 1:00 am was significantly greater than that at 9:00 am, which is consistent with the findings of previous studies. Patients with PD had decreased plasma concentrations of Asp, Glu, GABA, MT and epinephrine at 1:00 am and decreased plasma concentrations of Asp, Glu, DA and epinephrine at 9:00 am.
The plasma concentration of melatonin at 1:00 am was significantly lower in PD patients with RBD than in controls and PD patients without RBD (Fig. 2), whereas the levels of DA were elevated in PD patients with RBD compared with those in patients without RBD at this time point. However, no difference in DA levels was observed between the PD-RBD and control groups (Table S9). The plasma melatonin level at 1:00 am was negatively correlated with RBD (r = − 0.40, p = 0.0018), and the DA level was positively correlated with RBD (r = 0.29, p = 0.025) (Fig. 3).

Our study revealed a lower level of plasma melatonin in PD patients with RBD than in patients without RBD and healthy controls at 1:00 AM. In addition, the plasma melatonin level at this time was negatively correlated with RBD, suggesting that the decrease in the peripheral melatonin level in the early morning might be involved in RBD development. Previous studies using animal experiments reported that α-synuclein reduces acetylserotonin O-methyltransferase-mediated melatonin biosynthesis. Two previous studies reported that patients with PD presented reduced circulating melatonin levels. Furthermore, based on comprehensive clinical observations, 59.9% of 137 RBD patients reported improvements with melatonin treatment across various outcome measures in published studies. Thus, melatonin has been proposed as a preferable treatment for RBD. These results are consistent with previous findings and support the role of melatonin in the incidence of RBD.
EDS: Excessive daytime sleepiness
Videnovic et al. [11] reported that PD participants with EDS had a significantly lower amplitude of melatonin rhythm and 24-h melatonin area under the curve (AUC) than PD participants without EDS. In the present study, the absence of a change in the levels of melatonin among PD patients with or without EDS may have occurred because the patients were enrolled in the early stage of PD when circadian rhythm disruption was less severe than it was in the advanced stage.