#602

I have been reading up a bit on Parkinsons and talking to people.

Extract

we demonstrate that the cerebellum ages more slowly than other parts of the human body.

I am not a massive fan of epigenetic clocks, but I do think they have some use.

Interestingly in people with PD plasma levels of melatonin tend to be higher (particularly when treated), but CSF levels are lower.

https://jamanetwork.com/journals/jamaneurology/fullarticle/1833933

A significant difference in melatonin concentration was observed between lateral and third ventricles, with the highest levels in the third ventricle (8.75+/-2.75 pg/ml vs. 3.20+/-0.33 pg/ml, p=0.01). CSF aMT6s levels were similar in both ventricles and of low magnitude, less than 5 pg/ml.

Table1.

Summary of the Presumed Physiological Concentrations of Melatonin in Human CSF

Reference Year Melatonin (pg/ml)
Collection Time Collection Site Ages (Yr) Method Melatonin Form
Rousseau et al. [54] 1999 08:00-09:00h Lumbar cistern 25.3 ± 4.5 RIA Free 32.5 ± 25.5
Rousseau et al. [54] 1999 08:00-09:00h Lumbar cistern 25.3 ± 4.5 RIA Free 32.5 ± 25.5
Rousseau et al. [54] 1999 08:00-09:00h Lumbar cistern 25.3 ± 4.5 RIA Free 32.5 ± 25.5
Liu et al.[31] 1999 1-12 h after death Ventricular 76 ± 1.4 RIA Free 273 ± 47
Rizzo et al. [53] 2002 Night Lumbar cistern N/A HPLC Free + bound 28.6 ± 7.0
Rizzo et al. [53] 2002 Night Lumbar cistern N/A HPLC Free + bound 28.6 ± 7.0
Zhou et al. [72] 2003 1-12 h after death Ventricule 76 ± 2 RIA Free 280 ± 64
Longatti et al.[34] 2004 Day time Third ventricule N/A N/A Free 542
Longatti et al. [35] 2007 Day time Third ventricule 60.3 ± 17.9 HPLC Free + bound 442 ± 45
Seifman et al. [34] 2008 09:00h ventricule 30-74 ELISA Free 1.47 ± 0.35
Leston et al.[30] 2010 08:10-11:10 h Third ventricule 26-68 RIA Free 8.69 ± 2.75 (these are the people with PD)

Conclusion

So, we can see that Parkinsons patients have a materially lower melatonin concentration in the third ventricle of the CSF (which is where a lot of melatonin is injected from the pineal gland).

Either
a) A higher proportion is going into serum or
b) Less melatonin is being produced.

However, if one accepts that melatonin acts in cells to prevent damage to mitochondrial DNA and hence the reduction in efficiency of the mitochondria then it can be seen that

a) The higher levels of melatonin that arrive in the brain via the CSF act to reduce the rate at which neuronal mitochondria age
b) In people with PD this does not work as well hence brain cells age faster than they do in people without PD, but probably not as quickly as the rest of the body.

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#603

I have now done a post based upon the above

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#604

Thanks a lot John.

On the genetic vs environmental debate, these two papers might be of interest: Parkinson's disease - #532 by adssx

Regarding hypothetical cause 1 (“A higher proportion goes into serum than in non-PD patients”), it seems confirmed by this paper: Elevated Plasma Melatonin Levels Are Correlated With the Non-motor Symptoms in Parkinson’s Disease: A Cross-Sectional Study 2020

Compared with the healthy controls, the plasma melatonin levels were significantly higher in PD patients (12.82 ± 4.85 vs. 19.40 ± 4.23, P < 0.001). Plasma melatonin levels were significantly associated with the levodopa equivalent daily dose (r = −0.262, P < 0.05, n = 61). Higher plasma melatonin concentrations were detected in the negative cardiovascular symptom group than in the cardiovascular symptom group (20.13 ± 3.74 vs. 16.93 ± 3.74, P < 0.05). Higher plasma melatonin concentrations were detected in the non-sleep-disorders group than in the sleep disorders group (22.12 ± 5.93 vs. 18.86 ± 3.66, P < 0.05). In addition, the plasma melatonin concentration was higher in the group without gastrointestinal dysfunction than in the gastrointestinal dysfunction group (21.71 ± 4.44 vs. 18.35 ± 3.74, P < 0.05).
This study shows that patients with PD have a significant negative correlation with melatonin levels and levodopa equivalent doses, suggesting that the increased plasma melatonin level in PD patients may be related to the degeneration of dopaminergic neurons and the use of dopaminergic drugs. There is an interaction between the dopamine system and circadian rhythms. On the one hand, circadian genes regulate dopamine synthesis by regulating tyrosine hydroxylase. On the other hand, dopamine can regulate the expression of certain clock genes (Kawarai et al., 1997; Mcclung et al., 2005). Fertl, who found that compared to age-matched subjects, PD patients with melatonin secretion patterns evident in advance (Fertl et al., 1991), while the rhythm of this change may be due to central nervous system caused by levodopa therapy dopaminergic effects rather than the disease itself (Fertl et al., 1993). Studies on the circadian pattern of melatonin in PD patients have shown that dopaminergic treatment can significantly raise the level of plasma melatonin stage by stage, and the secretion of melatonin in PD patients with l-dopa-related motor complications increases during the day and significantly decreases at night. Studies have confirmed that dopamine plays an important role in maintaining the rhythmicity of the circadian system (Mendoza and Challet, 2014; Korshunov et al., 2017). Therefore, the increased melatonin level and the correlation with the equivalent dose of levodopa in PD patients may be related to the Circadian rhythm dysfunction of PD itself and the imbalance of the regulation of the dopaminergic system.

I’ll take more time reading the rest later but here is the analysis by ChatGPT (4o DeepResearch): ChatGPT - Parkinson's Disease Causes Analysis

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#605

I think it probably is the issue that physically less melatonin goes into the CSF and more into serum, but in a practical sense having less in the CSF is the thing to worry about because of the greater damage to mitochondrial DNA (in brain cells) that results.

There have been interesting reports about meditation improving the quality of the pineal and as a consequence reducing the rate of deterioration.

A physical event which caused say a (total or partial) blockage of the recess would fit with starting with symptoms of bad sleep (from reduced melatonin) followed by reports of cells malfunctioning.

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#606

It is quite a good analysis, but it still has substantial flaws. If we look at this argument which is used against my hypothesis:

Another environmental factor is head injury: a history of serious head trauma has been identified as a risk factor that might precipitate PD later​, possibly through inflammatory or oxidative pathways. All these factors suggest PD can be triggered or accelerated by external insults. Hemming’s hypothesis (melatonin/mtDNA damage) doesn’t directly incorporate toxins or injuries,

My argument is that potentially the switch between melatonin being injected via the pineal recess and melatonin being injected into serum would be substantiated by head injury being a cause of PD. Head injury could damage the pineal recess and cause a part or total blockage.

Hence although I don’t explicitly say head injury is potentially a cause of the way in which the pineal handles melatonin flow it is implicit, but used by the LLM as an argument against the hypothesis as opposed to an argument for the hypothesis.

There is also a general problem with the LLM in not following the link between mtDNA damage, Mitochondrial Membrane Potential, citrate efflux and histone acetylation with the consequent effects on gene expression and mRNA splicing.

It probably could be refined in a conversation with the LLM.

There are probably a number of different causes of a reduction of CSF melatonin, insults to the SCN, insults to the Pineal and potentially biochemical issues within the melatonin systems.

Still it does show the merits of using LLMs in looking at these things. It does manage to hunt up quite a bit of relevant material. If there are any arguments used by the LLM that you would suggest I respond to please indicate them.

#607

Also from the LLM

However, other studies found no significant difference in leukocyte telomere length between PD and controls

This sort of thing would not go down well in an exam paper.

#608

I wonder if from an analytical point of view we could/should not have to study three or for different causes of “parkinson symptoms”:
the adverse effects of butyrofeno type antipsychotic medication (haloperidol etc) that in the beginning of the treatment are often resolved by stopping or lowering this medication.
Toxicity caused by (agriculurally used) poisons or MPTP or 6-OH-DOPA that may be irreversible.
Juvenile onset parkinson caused by various recessive mutations.
Parkinson’s disease seen in the elderly with no clear cause then damage to mitochondria.
Despite having similar symptoms or even an identical final pathway there may be a different approach necessary???

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#609

It is entirely possible that there is a disease which is classified as Parkinsons that is not caused by a shortage of melatonin in the CSF.

In fact what we have here is a mechanism which could have itself a number of causes. The important thing about the mechanism, however, is that it makes it clear
a) That there is a continuing day to day deterioration as a result of metabolism.
b) That this can be mitigated (not with 1-2mg of melatonin, but with much more than that - how much I am not clear, but it can be seen that the levels of melatonin in CSF are normally quite high.
c) That mitophagy (in the brain) can to some extent reverse it.
d) That there are systems which can prop up the cells to reverse the symptoms.

It is also possible to find mechanisms which can reverse the cause of a reduction in CSF melatonin.

The LLM misses the point about melatonin which is that the cells produce melatonin themselves for the mitochondria. Additionally there is melatonin provided for the CSF to protect brain cells from damage as a result of metabolism.

#610
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#611

Why?

It’s based on this: No Evidence for Shorter Leukocyte Telomere Length in Parkinson’s Disease Patients 2010

As expected, age associated significantly with telomere length (p = .01). However, telomere length did not differ significantly between PD patients and controls (p = .54). Furthermore, extremely short telomeres were not more frequent in PD patients than in controls, as suggested in an earlier study. Our results do not support the concept of accelerated leukocyte telomere shortening in PD.

#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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