It’s an area that interests me in PD, along with calcium channels. The paper shows drug development targets. Immediate actionability is harder as it would be based on mechanistic speculation that is highly likely to fail. Basically I wanted to alert others who are interested in this area to an exciting paper. I expect big things from research in this direction.
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For those who have the time, this is an interesting look at cell transplantation and pathways in NDDs such as PD.
Stem Cell Pathways Targeting NDDs (via UCTV)
Evaluation of the neurotrophic peptide mixture in pathogenetic therapy of patients with Parkinson’s disease
This exploratory, single-group, open-label study investigated 17 patients with Parkinson’s disease (PD) using a pre-post design. Motor and non-motor outcomes were assessed through clinical scales, biochemical and genetic analyses, and machine learning models (Gradient Boosting Machines, Random Forests). After treatment with a neurotrophic peptide mixture, improvements were observed in daily activity (16%), cognition (11%), depression (10% reduction), and reactive anxiety (23% reduction). Biological changes included a 45% increase in platelet δ-granules, higher mitochondrial counts, elevated gene expression (notably BDNF in women, p = 0.046), and modulation of oxidative stress markers (17% reduction in TBARS, 30% increase in GSH). Machine learning identified BDNF and PINK1 expression, along with MOCA and MMSE scores, as key predictors of UPDRS improvement. These findings suggest that neurotrophic peptide therapy may influence clinical, structural, and molecular domains in PD. Larger, controlled trials are warranted to confirm therapeutic potential and clarify associations with cognitive and neurotrophic parameters.
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A new theory: Parkinson’s disease as a somato-cognitive action network disorder 2026
Press summary: Galaxy Brain Scientific’s Technology Enables Landmark Parkinson’s Study Published in Nature, Redefining Disease Mechanism
The researchers identified severe dysfunction in the somato-cognitive action network (SCAN)—a brain network essential for planning, coordinating, and executing actions—as the core feature of PD. In patients, this network shows abnormally high functional connectivity with deep brain regions, a signature not observed in other movement disorders such as essential tremor. “Our work shows that the disease is rooted in a much broader network dysfunction,” noted Prof. Hesheng Liu. “The SCAN is hyperconnected to key subcortical regions in PD, and this abnormal hyperconnectivity disrupts not only movement but also related cognitive and automatic functions.”
See also: PD as a SCAN Disorder
For too long, we have viewed Parkinson’s through a reductionist lens—a simple shortage of dopamine in a specific corner of the brain. However we can no longer deny that this disease is far more complex than a single chemical deficit could explain.
Yesterday’s paper in Nature from Profs Jianxun Ren, Nico Dosenbach, Hesheng Liu and colleagues, identifies the Somato-Cognitive Action Network (SCAN) as an intriguing structural “map” for what some have long suspected: Parkinson’s is not just a motor disorder; it is a systemic failure of communication.
If Parkinson’s is truly a “SCAN-opthy,” then our goal changes. We are no longer just chasing dopamine; we are tuning the instrument. We are learning to quiet the hyperconnectivity and restore the natural rhythms of the brain.
And a video summary of the paper:
https://twitter.com/hesheng3/status/2019413026839876035
Good summary as well: Hyperconnectivity of the SCAN – The Science of Parkinson's
To test this new treatment approach, the researchers conducted a clinical trial in which 18 Parkinson’s patients received the SCAN-targeted transcranial stimulation for two weeks and they were compared with 18 Parkinson’s patients who received stimulation to another brain region (this was the control group). The SCAN targeting treatment involved four 10-minute stimulation sessions per day with 50-minute intervals in between over the two weeks of the study (Click here to read more about the design of the study).
The SCAN targeted group showed a 56% response rate after two weeks, compared to just a 22% response rate in the control group. Response rate was measured using the standard clinical rating scale (the MDS-UPDRS-III).
Videos of the pre and post treatment performance has been posted on social media (Twitter) – click here, here and here if you would like to view these films.
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Reduced S1Ps/LPAs associate with impaired TCA cycle and motor deterioration.
FYI @John_Hemming
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While more than 30% of patients with Parkinson’s disease (PD) are prescribed statins, the impact of statin use on the progression of PD remains incompletely elucidated. We aimed to comprehensively investigate the impact of statin use on PD progression. We analyzed longitudinal data from the Parkinson’s Progression Markers Initiative (PPMI) to examine associations between statin use and clinical manifestations and cerebrospinal fluid (CSF) biomarkers. Mendelian randomization and Bayesian colocalization analyses were employed to assess genetic relationships between HMGCR inhibition (a proxy for statins) and PD phenotypes. Multi-omics analyses utilized postmortem substantia nigra RNA-seq data and CSF proteomics from living patients to explore potential mechanisms. In the PPMI cohort, statin use was associated with a faster cognitive decline among PD patients during longitudinal follow-up, which was partially mediated by reduced CSF Aβ42. Genetic analyses indicated detrimental effects of HMGCR inhibition on cognitive function, dyskinesia, and restless legs syndrome in PD. In addition, RNA-seq analysis of substantia nigra suggested that HMGCR expression gradually decreases with PD progression, showing significant reductions in moderate and advanced stages. Finally, CSF proteomics revealed that statin use was associated with 238 upregulated and 203 downregulated proteins in PD, among which 28 proteins were linked to cognitive decline and significantly enriched in pathways related to substantia nigra development and PD. Our study suggests that statins may accelerate cognitive decline in PD patients through mechanisms potentially involving reduced CSF Aβ42 levels, inhibition of HMGCR in the substantia nigra, and disruption of PD-related protein pathways.
n-th reminder to avoid statins in people with PD.
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Cholesterol has a function. I wonder if the same analysis could be done, but distinguishing between different statins and particularly those that target the liver rather than cholesterol more generally.
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Yeah, I’m afraid too much evidence has accumulated to show statins as negatives in the context of PD, regardless of the Japanese study observations. Time to put that on the shelf of “done deal”. The remaining question is about statins and NDDs in general and why there would (or would not) be differeces between effects in case of PD specifically. Is PD unique in this respect?
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used in many golf courses - father was a golfer and had PD
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These findings highlight the therapeutic potential of NALL for PD by its protective effects on α-synuclein pathology and synaptic function in vulnerable dopaminergic neurons.
Untargeted serum metabolomics and air pollution in Parkinson’s disease 2026
We identified 26 annotated metabolites and 23 metabolic pathways associated with air pollution exposure, particularly PM2.5 and traffic-related pollutants, in PD patients and controls. Metabolic profiles observed in controls aligned with prior studies, supporting external validity. Profiles in PD patients additionally indicated disease-specific disruptions. Air pollution was associated with inflammation-related lipid metabolism (e.g., increased leukotrienes; decreased eicosatrienoic acid and docosahexaenoic acids) and several amino acids (e.g., alanine, aspartate, and glutamate) in PD patients. We also found a reduction in tyrosine levels, possibly related to PD. Togethger, these findings suggest that air pollution may contribute to PD through inflammation, oxidative stress, and mitochondrial dysfunction.
Genetic interleukin-6 receptor blockade, chronic disease risk, and longevity: results from the women’s health initiative
See details at;
Japan approves stem-cell treatment for Parkinson’s in world first | News | djournal.com Japan approves stem-cell treatment for Parkinson's in world first
Results revealed a sex-specific effect of dairy intake, a significant association with a higher risk of Parkinson’s disease in males (HR 1.28, 1.05-1.56), whereas no association was observed in females (HR 1.02, 0.80-1.30). For milk intake only, estimates were 1.36 (0.97-1.90) for males and 1.19 (0.94-1.51) for females.
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Preprint + China + Tier 2 university + mice cell model
rapamycin restored TFEB nuclear translocation, reactivated the ALP, accelerated α-syn clearance, and abolished the increased toxicity of Irgm1-deficient microglia toward cocultured SH-SY5Y neurons after PFFs preexposure
Yeah, I guess. But the point is prevention of the conditions leading to alpha-synuclein misfolding in the microglia in the first place. By the time disequilibrium in calcium homeostasis appears it’s already too late (why I pay attention to calcium channels) - inflammation is downstream from this. I keep reading about how misfolding spreads prion-like, but the real crux is why the misfolding happens in the first place. The misfolding doesn’t just happen, it’s triggered. To be honest, I’m not impressed, sorry.
Alpha-synuclein in Parkinson’s disease and other synucleinopathies: from overt neurodegeneration back to early synaptic dysfunction
https://www.nature.com/articles/s41419-023-05672-9
“Abnormal forms of α-syn trigger selective and progressive neuronal death through mitochondrial impairment, lysosomal dysfunction, and alteration of calcium homeostasis not only in PD but also in other α-syn-related neurodegenerative disorders such as dementia with Lewy bodies, multiple system atrophy, pure autonomic failure, and REM sleep behavior disorder”
Older illustration:
Bent out of shape: α-Synuclein misfolding and the convergence of pathogenic pathways in Parkinson’s Disease
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My guess is the misfolding arises from changes in splicing.
chatGPT says
Also
Chat GPT:
Yes, it is plausible, but not as a simple universal rule.
Reduced histone acetylation can alter alternative splicing because chromatin state affects how RNA polymerase II moves through a gene and how splicing factors are recruited to nascent RNA. In general, histone acetylation tends to open chromatin, while reduced acetylation tends to make chromatin more compact and can change exon recognition during co-transcriptional splicing. That general chromatin–splicing link is well established.
The important caveat is that the effect is context-dependent. Reduced acetylation does not always mean “more aberrant splicing” in exactly the same direction for every exon. Some exons are promoted by slower elongation and tighter chromatin, others are skipped; the outcome depends on the local gene architecture, splice-site strength, recruited chromatin readers, and which splicing regulators are present. Reviews of the field consistently describe histone marks as part of a combinatorial “splicing code,” not a one-way switch.
So for the SNCA / α-synuclein isoforms discussed above, the careful answer is: reduced histone acetylation could contribute to aberrant splicing in principle, but I do not see strong direct evidence from these sources that reduced histone acetylation is an established primary driver of the specific SNCA splice isoforms linked to α-synuclein misfolding. The SNCA literature more clearly supports altered splicing itself and altered chromatin regulation of SNCA expression, while the direct bridge from histone hypoacetylation → specific SNCA isoform shift → misfolding remains less firmly demonstrated.
There is also an interesting bidirectional possibility: α-synuclein pathology may itself feed back on chromatin. Reviews cite work showing nuclear α-synuclein can inhibit histone acetylation and promote neurotoxicity, which raises the possibility of a vicious circle in which misfolded or overabundant α-synuclein worsens chromatin regulation, potentially including splicing regulation indirectly. That is biologically plausible, but still not the same as proving that reduced histone acetylation was the initial cause of the splice abnormality.
So my bottom line is:
Reduced histone acetylation is a credible upstream contributor to aberrant splicing, including potentially the splice-isoform changes relevant to α-synuclein biology, but it would be too strong to say it is likely the sole or proven cause of the SNCA aberrant splicing above. A better phrasing would be that it is a possible and biologically well-motivated modulator.
I can also set this out as a step-by-step mechanism from histone hypoacetylation → polymerase kinetics/chromatin readers → exon skipping/inclusion → α-synuclein isoform balance → aggregation risk.
And speaking of alpha-synuclein formation, based on the calcium channel pathway, there’s this extremely speculative look (bathroom reading):
The Role of Magnesium in Parkinson’s Disease: Status Quo and Implications for Future Research
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