This is a propaganda paper, but hey, I’ll take a PD useful drug from anywhere (if it works).
China ‘outpacing the US’ in biotech race to find cure for Parkinson’s disease
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SCMP isn’t really a “propaganda paper”. Of course, it’s not as independent as it used to be but it’s not the People’s Daily or Global Times either.
Anyway, I hope the Chinese will help in that fight!
Other interesting papers:
Dietary one‑carbon nutrients and genetic risk in Parkinson disease: a prospective cohort study 2026
Over a median 12.27-year follow-up of 202 171 participants, 1037 incident PD cases occurred. In multivariable-adjusted Cox models, compared with participants in the lowest quartile, those in the highest quartile of methionine, vitamin B6, folate, and vitamin B12 had a lower risk of PD (hazard ratio [HR] [95% confidence interval (CI)] = 0.83 [0.69-1.00], 0.75 [0.62-0.90], 0.71 [0.59-0.85], and 0.79 [0.65-0.94]). Genetically stratified analyses showed folate inversely associated with PD risk in the low‐risk group (HR [95% CI] = 0.65 [0.48-0.88]) (p for interaction = .48); vitamin B12 linked to lower risk in the high‐risk group (HR [95% CI] = 0.78 [0.63-0.99]) (p for interaction = .83); and vitamin B6 inversely associated across both strata (high‐risk HR [95% CI] = 0.77 [0.62-0.97]; low‐risk HR [95% CI] = 0.59 [0.44-0.80]) (p for interaction = .08).
Higher OCM nutrient intake might be inversely associated with PD risk. However, evidence regarding the independent contributions of dietary and genetic factors remains inconclusive.
Genetically predicted higher mitochondrial DNA copy number (mtDNAcn) is causally associated with lower Alzheimer’s disease (AD) and Parkinson’s disease (PD) risk.
AD genetic liability is causally associated with higher mtDNAcn, possibly as a compensatory response.
mtDNAcn is a potential early biomarker of mitochondrial dysfunction in AD/PD.
This one is for you @John_Hemming
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I think the point about mitochondrial dysfunction is that it is like a car crashing. It does not really matter how many different examples people study of what happens when a car crashes such as into a wall, a river, a sea, a nuclear power station or a tree (etc), what people are not studying is what causes the car to crash.
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Preprint α-Synuclein (α-Syn) accumulation is a central pathological feature of Parkinson’s disease, yet its impact extends beyond proteostasis failure. Here, we identify intracellular pH dysregulation as a previously unrecognized consequence of α-Syn overexpression in neuronally differentiated SH-SY5Y cells. α-Syn promotes cytosolic acidification by stabilizing the acid-loading anion exchanger AE2 (SLC4A2) through mTOR-dependent impairment of lysosomal degradation. Pharmacological modulation of this pathway revealed opposite effects on AE2 turnover: rapamycin rescued, whereas bafilomycin A1 exacerbated, AE2 accumulation, in parallel with reciprocal changes in intracellular pH (alkalinization with rapamycin and further acidification with bafilomycin). Because acidic conditions favor misfolding and aggregation of this intrinsically disordered protein, α-Syn–driven acidification may establish a self-reinforcing pathogenic loop that fuels disease progression. Our findings identify AE2-mediated acid loading as a central driver of α-Syn–induced cellular dysfunction, establishing intracellular pH dysregulation as a possible core pathogenic mechanism in synucleinopathies.
The rescue achieved by rapamycin-mediated mTORC1 inhibition is particularly informative in this context. The preferential recovery of pHi observed in SNCA cells after rapamycin treatment indicates that mTOR hyperactivation is the primary signal maintaining lysosomal dysfunction. This is consistent with reports that pathological α-synuclein disrupts the TSC1–TSC2 complex to sustain mTORC1 activity and with the broader literature linking mTOR dysregulation to impaired lysosomal biogenesis and autophagic clearance in patient tissues (8–10). Restoration of AE2 turnover following mTORC1 inhibition further supports the conclusion that reactivation of autophagic flux is sufficient to normalize intracellular acid balance.
Macroautophagy activator rapamycin reversed (G603R) Lrp10-induced increment of α-synuclein, death of SN dopaminergic cells and PD locomotor disability in Lrp10G603R/+ mouse.
That is after the car crashed into the tree and the tree fell over damaging a house.
And rapamycin doesn’t cross the BBB, so… of course, this is mice, but the other paper (“rapamycin rescues”) poses the same question. If this is down to mTORC1, I wish they would look at everolimus effect on alpha-syn and dopa cells compared to sirolimus.
On a different note I was looking at alpha-syn and prodromal PD, and wondering what were the differences between early onset vs late onset PD. Frustratingly, I cannot find much - most is in 60+
Neuronally Derived Extracellular Vesicle α-Synuclein as a Serum Biomarker for Individuals at Risk of Developing Parkinson Disease
https://jamanetwork.com/journals/jamaneurology/fullarticle/2812433
“A number of nonmotor symptoms, such as rapid eye movement sleep behavior disorder (RBD), olfactory loss, or autonomic dysfunction can manifest during the prodromal phase and are associated with higher risk of phenoconversion to PD.[1]Isolated RBD (iRBD) is the strongest predictor of α-synucleinopathy with more than 80% of participants converting to PD, dementia with Lewy bodies (DLB), or multiple system atrophy (MSA) within 12 years.[2]”
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If PD is the failure of dopaminergic neurons then prodomal PD is where they are failing a bit and the full blown disease is when they are failing badly.
I would argue that the subtleties between the symptoms of these do not give us that much information as to the cause (which I believe to be a failure of the mitochondrial homeostasis much like accelerated aging).
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Anyone looked into capsaicin for Parkinson’s? According to the following studies:
Capsaicin increases the number of dopaminergic neurons and the expression of the enzyme tyrosine hydroxylase (TH) in those neurons.
Increasing TH expression will increase the dopamine output despite reduced surviving neurons.
This in combination with the supposed increase in dopaminergic neurons which is quite miraculous this should be an effective treatment. I do have my doubts on how effective this would be but I think it would be a useful ancillary supplement for anyone with any condition of dopaminergic insufficiency. Though this study only confirms the increase in dopaminergic neuron amount and TH expression in the substantia nigra segment of the brain.
It also had impressive anti-inflammatory effects where it reduced certain ROS and key cytokines including TNF-α, IL-1β, IL-6.
It also seemed to increase glutathione production in the brain but this was in a cell culture not in an animal or human study.
Another study showed it reduced beta amyloid plaque production. There was an association between higher spicy food consumption and higher cognitive ability + lower beta amyloid plaque levels.
But then a follow up study that went on for 15 years that addressed the claims of the previous study showing the association of higher spicy food consumption and higher cognitive ability actually showed the opposite. So perhaps moderate chili intake is the answer.
“The main symptoms of Parkinson’s disease are tremor, rigidity, and bradykinesia, all of which are caused by the degeneration of tyrosine hydroxylase positive dopaminergic neurons in the substantia nigra. Consequently, there is less dopamine in the striatum because substantia nigra neurons project to the striatum. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and its active metabolite MPP+ (1-methyl-4-phenylpyridinium), are toxic chemical compounds that cause neurodegeneration of substantia nigra neurons. Therefore, MPTP and MPP+ treated animals are used as models of Parkinson’s disease [31,32].
Different interconnected mechanisms cause substantia nigra neurodegeneration in Parkinson’s disease, for example, alpha-synuclein aggregation, mitochondrial dysfunction, and microglial activation [31,32]. It was found that activated microglia contribute to the neurodegeneration process in the substantia nigra by producing oxidants and proinflammatory cytokines [31].
It was repeatedly found that capsaicin reduced neurodegeneration and motor impairment in animal models of Parkinson’s disease [12,31,33,34,35,36]. This compound exerted beneficial effects on Parkinson’s disease by decreasing microglial activation and reducing neuroinflammation [12,31,35,37]. These findings are summarized in Figure 3.
The beneficial effects of capsaicin in Parkinson’s disease are shown in simplified form. Capsaicin administration increases the number of dopaminergic neurons in the substantia nigra and the expression of tyrosine hydroxylase in these neurons. Consequently, there is more dopamine in the striatum. Moreover, after capsaicin treatment, microglial cells in the substantia nigra produce fewer oxidants and inflammatory cytokines. Left panel—before capsaicin treatment, right panel—after capsaicin treatment.
In an MPTP mouse model of Parkinson’s disease, it was found that intraperitoneal application of capsaicin (0.5 mg/kg) increased the number of dopaminergic (tyrosine hydroxylase positive) neurons in the substantia nigra. This effect was dependent on TRPV1 channels. The authors also found that capsaicin improved motor impairment and suggested that one of the mechanisms of these beneficial effects was that this compound decreased the production of reactive oxygen species and proinflammatory cytokines (TNF-α and IL-β) by activated microglia [31]. Similar results were obtained by a different laboratory in a lipopolysaccharide rat model of Parkinson’s disease. The authors found that intraperitoneal capsaicin (1 mg/kg) reduced neurodegeneration in the substantia nigra. In the presence of the tested compound, microglial cells shifted from a proinflammatory to an anti-inflammatory state and produced fewer oxidants and proinflammatory cytokines (IL-1β and IL-6). These neuroprotective effects were dependent on TRPV1 channels because they were reduced after administration of a selective TRPV1 inhibitor, capsazepine [35].
Not only microglial cells but also astrocytes (a different type of glial cell) are influenced by capsaicin in Parkinson’s disease [36]. It was found in an MPP+ animal model that capsaicin applied intraperitoneally (1 mg/kg; a single injection/day for 7 days) activated TRPV1 receptors on astrocytes in the substantia nigra. TRPV1 receptors activation enhanced the production of a ciliary neurotrophic factor by astrocytes which increased tyrosine hydroxylase activity in the substantia nigra and dopamine levels in the striatum [36]. Capsaicin also caused behavioral recovery in MPP+ animals. In a different study from the same laboratory, it was found in the same model of Parkinson’s disease that activated microglia produced fewer reactive oxygen species in the substantia nigra after intraperitoneal administration of capsaicin (1 mg/kg). Microglia-derived oxidative stress was reduced by a ciliary neurotrophic factor produced by capsaicin-stimulated astrocytes in the substantia nigra [12]. This effect of capsaicin reduced neurodegeneration and decreased motor impairment in MPP+ rats.
Alpha-synuclein deposition is an important feature of Parkinson’s disease [32]. A protective role of dietary capsaicin (20, 40, 80 and 100 μM for 24 days) against Parkinson’s disease was reported in flies expressing human alpha-synuclein. It was found that capsaicin increased dopamine content, reduced oxidative stress markers, and enhanced free radical scavenging potential in brains obtained from flies with Parkinson’s disease [38].
To summarize, capsaicin treatment reduces neurodegeneration and improves behavioral outcomes in different animal models of Parkinson’s disease. The important mechanism of this effect is that this compound reduces oxidants and proinflammatory cytokines production by activated microglia. This process is shown schematically in Figure 3.” - Beneficial Effects of Capsaicin in Disorders of the Central Nervous System Beneficial Effects of Capsaicin in Disorders of the Central Nervous System - PMC
“The present study aimed to identify the gene expression changes conferred by capsaicin in the cell model of 6-OHDA-induced Parkinson’s disease, to disclose the molecular mechanism of action of capsaicin. We used capsaicin-treated and paraffin-embedded wax blocks containing substantia nigra tissue from 6-OHDA-induced Parkinson’s disease rats to analyze transcriptional changes using Affymetrix GeneChip Whole Transcript Expression Arrays. A total of 108 genes were differentially expressed in response to capsaicin treatment, and seven of these genes were selected for further analysis: Olr724, COX1, Gsta2, Rab5a, Potef, Actg1, and Acadsb, of which Actg1 (actin gamma 1) was down-regulated and Gsta2 (Glutathione S-transferase alpha 2) was up-regulated. We successfully overexpressed Actg1 and Gsta2 in vitro. CCK-8 detection and flow cytometry demonstrated that overexpression of Actg1 and Gsta2 increased apoptosis in the 6-OHDA-induced Parkinson’s disease cell model. The imbalance between Actg1 and Gsta2 may be one of the mechanisms of cell damage in Parkinson’s disease (PD). Capsaicin can protect the cells and reduce the apoptosis rate by regulating Actg1 and Gsta2.” - Regulation of Actg1 and Gsta2 is possible mechanism by which capsaicin alleviates apoptosis in cell model of 6-OHDA-induced Parkinson’s disease https://portlandpress.com/bioscirep/article/40/6/BSR20191796/225257/Regulation-of-Actg1-and-Gsta2-is-possible
“Previous studies suggest that there is a geographic overlap between AD incidence and spicy food consumption. We previously reported that capsaicin-rich diet consumption was associated with better cognition and lower serum Amyloid-beta (Aβ) levels in people aged 40 years and over. In the present study, we found that intake of capsaicin, the pungent ingredient in chili peppers, reduced brain Aβ burden and rescued cognitive decline in APP/PS1 mice. Our in vivo and in vitro studies revealed that capsaicin shifted Amyloid precursor protein (APP) processing towards α-cleavage and precluded Aβ generation by promoting the maturation of a disintegrin and metalloproteinase 10 (ADAM10). We also found that capsaicin alleviated other AD-type pathologies, such as tau hyperphosphorylation, neuroinflammation and neurodegeneration. The present study suggests that capsaicin is a potential therapeutic candidate for AD and warrants clinical trials on chili peppers or capsaicin as dietary supplementation for the prevention and treatment of AD.” - Capsaicin consumption reduces brain amyloid-beta generation and attenuates Alzheimer’s disease-type pathology and cognitive deficits in APP/PS1 mice Capsaicin consumption reduces brain amyloid-beta generation and attenuates Alzheimer’s disease-type pathology and cognitive deficits in APP/PS1 mice - PMC
“We aimed to examine the association between chili intake and cognitive function in Chinese adults. This is a longitudinal study of 4852 adults (age 63.4 ± 7.7) attending the China Health and Nutrition Survey during 1991 and 2006. Cognitive function was assessed in 1997, 2000, 2004 and 2006. In total, 3302 completed cognitive screening tests in at least two surveys. Chili intake was assessed by a 3-day food record during home visits in each survey between 1991 and 2006. Multivariable mixed linear regression and logistic regression were used. Chili intake was inversely related to cognitive function. In fully adjusted models, including sociodemographic and lifestyle factors, compared with non-consumers, those whose cumulative average chili intake above 50 g/day had the regression coefficients (and 95% CI) for global cognitive function of −1.13 (−1.71–0.54). Compared with non-consumers, those with chili consumption above 50 g/day had the odds ratio (and 95% CI) of 2.12(1.63–2.77), 1.56(1.23–1.97) for self-reported poor memory and self-reported memory decline, respectively. The positive association between chili intake and cognitive decline was stronger among those with low BMI than those with high BMI. The longitudinal data indicate that higher chili intake is positively associated with cognitive decline in Chinese adults in both genders.” - High Chili Intake and Cognitive Function among 4582 Adults: An Open Cohort Study over 15 Years https://www.researchgate.net/publication/333413321_High_Chili_Intake_and_Cognitive_Function_among_4582_Adults_An_Open_Cohort_Study_over_15_Years
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Preprint CUHK: Neuroprotective Effect of Melatonin in Isolated Rapid Eye Movement Sleep Behavior Disorder
Methods: This longitudinal cohort study included 194 video-polysomnography-confirmed patients with iRBD from a single center in Hong Kong from 2007 to 2023, with a median follow-up of 5·5 years. The primary exposure of interest was the continued use of melatonin as per prescription records versus discontinued use. The primary outcome was phenoconversion risk to PD or DLB. Secondary outcomes included longitudinal changes in neurodegenerative signs/biomarkers using generalized linear mixed-effects models. Melatonin exposure was further handled as a time-varying covariate in survival analyses, and the minimal effective dosage was estimated via penalized splines.
Findings: Among 194 patients (mean [SD] age, 66·2 [7·3] years; 140 [72·2%] male), continued melatonin use was associated with a significantly lower risk of phenoconversion (adjusted hazard ratio [aHR], 0·47; 95% CI, 0·26-0·83), particularly for DLB (aHR, 0·28; 95% CI, 0·10-0·76). This association persisted after propensity score matching and weighting. As a time-varying covariate, melatonin showed a dose-dependent protective effect (aHR, 0·91; 95% CI, 0·85-0·99 for any phenoconversion; aHR, 0·88; 95% CI, 0·79-0·99 for DLB), with an estimated minimal effective dose of 7·0 mg. Continued melatonin use was also associated with slower declines in RBD symptom severity, global cognition, color vision, visuospatial/attentional function, and motor coordination.
Interpretation: Continued melatonin use was associated with a reduced risk of phenoconversion to overt α-synucleinopathies in patients with iRBD, suggesting a potential neuroprotective effect in this high-risk population.
Beyond its well-established symptomatic efficacy and favorable safety profile, melatonin may serve as a feasible, low-risk neuroprotective strategy for individuals in the prodromal stage of neurodegeneration.
This HK team somehow replicates previous German findings: Parkinson's disease - #679 by adssx
@John_Hemming vindicated once again? Poke @CronosTempi you might want to increase your melatonin dose?
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Thank you. The question that needs answering is whether a high enough dose of melatonin enables the normal range of mitophagy to increase ⟨ΔΨm⟩
By the way, there are those ongoing trials:
- Disease Modifying Potential of 5mg of Melatonin on Cognition and Brain Health in Aging, NCT03954899
- Effect of Melatonin on Oxidative Stress Parameters in Levodopa-Treated Parkinson’s Disease Patients, NCT07375693
- Effects of 3-Month Melatonin Treatment on Regional Cerebellar Structure and Blood Biomarkers in Alzheimer’s Disease Spectrum, NCT06756828
These are 5, 10 and 2 mg of melatonin. I think the mistake made by people in looking at dosing is that they don’t take into account the fact that a lot of melatonin (ordinarily) is injected directly into the CSF by the pineal. Hence the brain has much higher concentrations than the serum peak.
Hence I think these doses are really quite low. They may still have an effect. I would like to audit the calculations that are done identifying the dosing.
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