Parkinson's disease

#943

Potential new mechanism of action explaining PD? Scientists watch Parkinson’s protein drill holes in brain cells 2025

Until now, most research has focused on the large aggregates known as fibrils, which are visible in brain tissue from patients with Parkinson’s. But a new study focuses on smaller, less understood, and more toxic structures: α-synuclein oligomers. According to the researchers, these are the ones that drill microscopic holes in the membranes of nerve cells.

And a potential therapeutic avenue according to this Swiss-Danish preprint: Ambroxol displaces α-synuclein from the membrane and inhibits the formation of early protein-lipid coaggregates 2025

Using kinetic analyzes of DMPS-induced aggregation curves of αS, we discovered that ABX specifically inhibits the primary nucleation step of the process of lipid-protein coaggregation and decreases the rate of formation of early oligomers.

Good papers on DNA damage @John_Hemming and compensatory mechanisms:

A blood-based DNA damage signature in patients with Parkinson’s disease is associated with disease progression 2025

Aging is the main risk factor for Parkinson’s disease (PD), yet our understanding of how age-related mechanisms contribute to PD pathophysiology remains limited. We conducted a longitudinal analysis of blood samples from the Parkinson’s Progression Markers Initiative cohort to investigate DNA damage in PD. Patients with PD exhibited disrupted DNA repair pathways and biased suppression of longer transcripts, indicating age-related, transcription-stalling DNA damage. Notably, at the intake visit, this DNA damage signature was detected only in patients with more severe progression of motor symptoms over 3 years, suggesting its potential as a predictor of disease severity. We validated this signature in independent PD cohorts and confirmed increased DNA damage in peripheral blood cells and dopamine neurons of the substantia nigra pars compacta in postmortem PD brains. Our study sheds light on an aging-related mechanism in PD pathogenesis and identifies potential markers of disease progression, providing a diagnostic platform to prognosticate disease progression.

Indeed, studying mouse models of genome instability, we found that mild rather than pronounced DNA repair defects elicit a dopaminergic phenotype that recapitulates PD, also due to a pronounced adaptive, antioxidant response elicited by severe transcription-stalling DNA damage. Interestingly, our data indicate that the suppression of DNA repair pathways is reversed at more advanced stages of pathogenesis when surrogate measures of DNA damage instead appear. This evidence points to an interplay between the kinetics of DNA damage accumulation and the activation of repair mechanisms. Here, the progressive accumulation of DNA damage during pathogenesis may stimulate the activation of DNA repair pathways, which are initially downregulated. This possibility is consistent with our previously published observations indicating that chronic α-synuclein stress activates the DNA damage response

CSF Mitochondrial DNA: Biomarker of Body Composition and Energy Metabolism in Parkinson’s Disease 2025

CSF cf-mtDNA levels, defined as the copy numbers of two regions of the mtDNA circular molecule (mt64-ND1 and mt96-ND5), were quantified in 44 PD patients and 43 controls using multiplex digital PCR. The mt96-ND5/mt64-ND1 ratio was calculated to estimate mtDNA deletion burden. Associations with clinical features, body composition, serum nutritional markers, and plasma energy metabolism-related organic acids were examined. Generalized linear models (GLMs) were performed to adjust for confounders.
CSF mt64-ND1 and mt96-ND5 levels were lower in PD patients than controls (p = 0.002, p = 0.001), while the mt96-ND5/mt64-ND1 ratio showed no group difference. GLM analysis identified body composition indices and serum albumin as key determinants of cf-mtDNA levels. Subgroup analysis showed lower cf-mtDNA levels in PD patients with preserved body composition and nutritional status. The mt96-ND5/mt64-ND1 ratio displayed a biphasic association with body composition and an inverse correlation with plasma 2-ketoglutaric acid, suggesting a link to energy metabolism.
CSF cf-mtDNA levels are reduced in PD and influenced by body composition and nutritional status, supporting their role as a metabolic biomarker. While the cf-mtDNA deletion ratio remained unchanged, its association with body composition suggests a complex interplay between mitochondrial integrity and metabolism. These findings highlight the relevance of cf-mtDNA in PD pathophysiology and the need for further study.

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#944

What is the Ambroxol story, has it failed once, being tested again, does it need to be coupled with some other agent, just being a chaperone, is it helpful at some stage, but not later. Increasing GCase, at what dosage in humans.

Has this been posted? Search didn’t find it. Old paper, nonhuman primates.

Oral ambroxol increases brain glucocerebrosidase activity in a nonhuman primate

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#945

Many RCTs in progress. Results soon.

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#948

Article combining our favorite topics (mtDNA, hypoxia, and PD): Hypoxia and TTR dysregulation in astrocytes from Parkinson’s disease with a specific mitochondrial haplogroup: A single-cell analysis 2025

Mitochondrial DNA variants have been linked to cognitive progression in Parkinson’s disease; however, the mechanisms by which mitochondrial DNA variants or haplogroups contribute to this process remain unclear. In the present study, we analyzed single-nucleus RNA sequencing data from 241 post-mortem brain samples across five regions to investigate the dysregulatory mechanisms associated with mitochondrial DNA haplogroup H and haplogroups J, T, and U#.
Pathway analysis highlighted abnormal hypoxic and reactive oxygen species environments in astrocytes, whereas protein complex analysis revealed a consistent and significant elevation in ribosomal subunit complexes within the astrocyte subtypes.
Our findings suggest that mitochondrial DNA haplogroup H may drive Parkinson’s disease cognitive progression through aberrant TTR expression and a hypoxic environment.

Gut microbial production of imidazole propionate drives Parkinson’s pathologies 2025

Parkinson’s disease (PD) is characterized by the selective degeneration of midbrain dopaminergic neurons and aggregation of α-synuclein. Emerging evidence implicates the gut microbiome in PD, with microbial metabolites proposed as potential pathological mediators. However, the specific microbes and metabolites involved, and whether gut-derived metabolites can reach the brain to directly induce neurodegeneration, remain unclear. Here we show that elevated levels of Streptococcus mutans (S. mutans) and its enzyme urocanate reductase (UrdA), which produces imidazole propionate (ImP), in the gut microbiome of patients with PD, along with increased plasma ImP. Colonization of mice with S. mutans harboring UrdA or Escherichia coli expressing UrdA from S. mutans increases systemic and brain ImP levels, inducing PD-like symptoms including dopaminergic neuronal loss, astrogliosis, microgliosis, and motor impairment. Additionally, S. mutans exacerbates α-synuclein pathology in a mouse model. ImP administration alone recapitulates key PD features, supporting the UrdA–ImP axis as a microbial driver of PD pathology. Mechanistically, mTORC1 activation is crucial for both S. mutans- and ImP-induced PD pathology. Together, these findings identify microbial ImP, produced via UrdA, as a direct pathological mediator of the gut-brain axis in PD.

The interesting bit is the mechanism:

Gut-colonized S. mutans induces dopaminergic neurotoxicity and motor dysfunction via mTORC1 activation

While imidazole propionate exerted relative regional specificity in inducing brain pathology in vivo, mTORC1 activation was still elicited in primary cortical neurons following imidazole propionate treatment in vitro, as evidenced by the phosphorylation of S6K1 at T389 and subsequent downstream signaling events, such as serine phosphorylation of IRS1 (Fig. 3c). These effects were effectively blocked by the mTORC1 inhibitor rapamycin or p38γ inhibitor pirfenidone (Fig. 3c), in line with the previous findings in primary hepatocytes9,14. Additionally, imidazole propionate treatment of primary cultured cortical neurons resulted in ~50.3% neurotoxicity, which was effectively blocked by both rapamycin and pirfenidone treatments (Supplementary Fig. 3c). These results underscored the key role of the imidazole propionate/p38γ/mTORC1 pathway in imidazole propionate-induced neuronal toxicity.

To investigate whether mTORC1 inhibition can reverse gut-colonized S. mutans-induced PD pathology, we depleted the gut microbiome of C57BL/6 N mice by administering an antibiotic cocktail (Abx) via oral gavage twice daily for seven days (Fig. 3d). This method, as described previously10,21, effectively reduces the bacterial load (Supplementary Fig. 3d), as monitored by a colony formation assay with fecal samples. Starting on the 8th day, the antibiotic-treated mice were gavaged with S. mutans (109 CFU/mouse) daily for 14 days with or without an intraperitoneal injection of rapamycin (Fig. 3d). S. mutans was undetectable before (Pre-Abx) and seven days after antibiotic treatment (Post-Abx), but its levels markedly increased following colonization. Rapamycin did not affect S. mutans colonization efficiency, as demonstrated by absolute quantification of the S. mutans 16S rRNA gene (Supplementary Fig. 3e). These treatments did not affect body weight or cecal weight (Supplementary Fig. 3f, g). Interestingly, S. mutans-induced decrease in brain weight in the antibiotic-treated mice was reversed by rapamycin treatment (Supplementary Fig. 3h). Although antibiotic-treated mice exhibited higher plasma and brain imidazole propionate levels than GF mice (Figs. 1j, k and 3e, f), S. mutans colonization further increased these levels to ~400 nM (Fig. 3e). Similarly, brain imidazole propionate concentration increased robustly in antibiotic-treated mice colonized with S. mutans (Fig. 3f). Importantly, rapamycin treatment did not reduce the elevated levels of imidazole propionate induced by S. mutans in plasma and brain (Fig. 3e, f). Precursor urocanate levels were similar among all experimental groups and were not affected by S. mutans colonization or rapamycin treatment (Supplementary Fig. 3i, j). The increase in S6 and 4E-BP1 phosphorylation induced by S. mutans in the dopaminergic neurons of the substantia nigra was almost completely reversed by rapamycin treatment (Fig. 3g, Supplementary Fig. 3k), despite comparable elevations in imidazole propionate in the brain of S. mutans-colonized mice with or without rapamycin (Fig. 3f). In support of our hypothesis of mTORC1-dependent neurotoxicity, rapamycin treatment (mTORC1 inhibition) effectively prevented 4E-BP1 phosphorylation, dopaminergic neurodegeneration, astrogliosis, and microgliosis in the ventral midbrain, as well as the loss of dopaminergic processes in the substantia nigra reticularis and dopaminergic axon terminals in the striatum (Fig. 3h, i, and Supplementary Fig. 3k, l, m). Rapamycin also reversed motor dysfunction induced by S. mutans colonization in antibiotic-treated mice (Fig. 3j).

Considering the increased risk of developing PD in individuals with diabetes and the association of this condition with increase in PD severity33, it is plausible that microbial imidazole propionate serves as a potential link between diabetes and PD. This hypothesis is based on our previous findings regarding its role in diabetes14. Based on the recent report demonstrating the interaction between p38γ and α-Syn and the translocation of p38γ to neuronal cell bodies in patients with dementia with Lewy bodies and PD34, the reversal of imidazole propionate-induced neurotoxicity by the p38γ inhibitor pirfenidone suggests a potential therapeutic option for individuals with elevated imidazole propionate levels and consequently high risks of diabetes and PD.

They write “the reversal of imidazole propionate-induced neurotoxicity by the p38γ inhibitor pirfenidone” but they only proved reversal with rapamycin. Weird. In any case @John_Hemming & @DrFraser it shows (again) that rapamycin could theoretically reverse some PD symptoms via the gut axis.

Pirfenidone: Pirfenidone - Wikipedia

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Changes in Plasma Aβ42/40 Ratio and p-Tau181 in Amyloid-Positive Patients Treated with Sirolimus
Oral Bacteria May Trigger Parkinson's Disease - Neuroscience News
#949

Answer:

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image1162×1388 170 KB

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#950

Protective role of Bre1 in mitochondrial function and energy metabolism in Drosophila models of Parkinson’s disease 2025

Bre1 encodes an E3 ubiquitin ligase, with the discovery of Bre1’s role in repairing mitochondrial damage, further investigation into its implications for PD is warranted.
Bre1 encodes an E3 ubiquitin ligase, which mediates the ubiquitination machinery that plays a broad range of biological roles in various aspects of DNA replication and repair
Recent studies have indicated that Bre1 is implicated in regulating Rad51 to participate in mitochondrial mtDNA repair, thereby mitigating mitochondrial damage resulting from the accumulation of ROS
Bre1 overexpression
Bre1 OE improves glycolysis and the key TCA cycle regulating enzyme OGDH
The TCA cycle and the respiratory chain are two pivotal components of intracellular energy metabolism that function synergistically to convert nutrients into ATP. Oxoglutarate dehydrogenase (OGDH) is a key regulatory point in the TCA cycle [65]. Responsible for catalyzing the dehydrogenation and decarboxylation of α-ketovalerate into succinyl-coenzyme A [66] ‌. Studies have shown that a toxic metabolite of MPTP inhibits alpha-ketoglutarate dehydrogenase activities in mitochondria [67]. Our findings indicate that Bre1 OE significantly enhanced the transcriptional activity of OGDH. Besides, in the context of antioxidant stress, Bre1 reinstates the functionality of SOD and diminishes the level of ROS. These findings are consistent with the transcriptome sequencing data and validate the role of Bre1 in augmenting the glycolytic pathway, TCA cycle and antioxidant.
In conclusion, Bre1 is involved in repairing mitochondrial morphology, attenuating the damage induced by reactive oxygen species (ROS), restoring mitochondrial functionality, promoting energy metabolism, enhancing ATP levels, and thereby preventing neurodegeneration in PD and improving motor function. It also indicates that overexpressed Bre1 may present a potential therapeutic strategy for the PINK1 mutant form of PD. Further investigation will be conducted to elucidate the molecular mechanism through which Bre1 impacts mitochondria in future studies.

@John_Hemming: Interesting therapeutic avenue to improve mtDNA repair?

ChatGPT and other LLMs only suggest resveratrol for up-regulating the Bre1 homolog (RNF20). Hypoxia/HIF-1 can recruit RNF20/40 to hypoxia-induced genes (rather than expression upregulation).

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#951

Turkish paper + rat model so low quality: Autophagy activation ameliorates cognitive deficits and alpha-synuclein pathology in an adeno-associated viral vector mediated rat model of Lewy body disorders 2025

The dual-site AAV injection model offers advantage to study cognitive deficits in LBD.
Rapamycin reversed spatial learning deficits induced by a-syn overexpression.
Rapamycin preserved synaptic integrity in both hippocampus and striatum.
Rapamycin reduced a-syn pathology in all layers of CA2 and partially in CA3.
Autophagy was differentially regulated within the striatum and hippocampus.

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#952

Another -tinib for LBD: Safety, tolerability and potential biomarkers of vodobatinib in patients with dementia with Lewy bodies 2025

Abl kinase inhibitor vodobatinib was investigated in dementia with Lewy bodies and was safe.
The number of falls was reduced and CSF Aβ42/Aβ40 was significantly altered in the vodobatinib compared to placebo groups.
Larger trials and longer treatment periods are warranted

:warning: Also by Charbel Moussa of Georgetown University… :warning:

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#953
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#954

Worth listening to, touches upon PD, but NDD more generally.

#955

Not PD but a related disease: Patient-Derived Neurons Exhibit α-Synuclein Pathology and Previously Unrecognized Major Histocompatibility Complex Class I Elevation in Mitochondrial Membrane Protein–Associated Neurodegeneration 2025

Mitochondrial membrane protein–associated neurodegeneration (MPAN) from the neurodegeneration with brain iron accumulation (NBIA) family is a rare neurodegenerative disease marked by α-synuclein aggregation, brain iron accumulation, and midbrain dopaminergic neuron degeneration.

They found that Tanganil and Aqneursa helped:

Next, we used the modified amino acid AL, specifically the racemate acetyl-DL-leucine (ADLL) and the bioactive enantiomer acetyl-L-leucine (ALL), to modulate this pathological feature. Both ADLL and ALL reduced MHC-I levels in patient mDA neuronal cultures (Fig. 2E), offering a strategy for reducing pathological triggers of disease.

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#956

New type of PD model: A human striatal-midbrain assembloid model of alpha-synuclein propagation 2025

Animal models of the pathology of Parkinson’s disease (PD) have provided most of the treatments to date, but the disease is restricted to human patients. In vitro models using human pluripotent stem cells (hPSCs)-derived neural organoids have provided improved access to study PD etiology. This study established a method to generate human striatal-midbrain assembloids (hSMAs) from hPSCs for modeling alpha-synuclein (α-syn) propagation and recapitulating basal ganglia circuits, including nigrostriatal and striatonigral pathways.
Human striatal organoids and midbrain organoids were generated using a stepwise differentiation protocol from hPSCs, and both regionalized neural organoids were assembled to form hSMAs, mimicking some basal ganglia circuits. Both the nigrostriatal and striatonigral pathways were present and the neurons such as dopaminergic (DA) neurons and GABAergic neurons were electrophysiologically active in the hSMAs. hSMA development in the presence of increased α-syn from SNCA overexpression, induced nigrostriatal system damage, which is typical of the disease. Using the α-syn-linker-mKO2 reporter and a bimolecular fluorescence complementation system, we demonstrated that fluorescent α-syn was retrogradely transported from the striatal area to DA neurons of the midbrain area and exhibited α-syn aggregates and Lewy body-like inclusions. Furthermore, phosphorylated and detergent-resistant α-syn aggregates, similar to pathological form in human patients, was accumulated in midbrain area of hSMAs. Treatment with protein aggregation inhibitor (Anle138b) and autophagy inducer (Rapamycin) reduced α-syn aggregation, indicating potential of hSMAs for drug testing.
This study established hSMAs as a novel platform for modeling PD, demonstrating α-syn propagation and associated neural pathologies. These assembloids offer significant potential for developing therapeutic strategies and understanding the mechanisms of PD progression.

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#957

The electrical field across the membrane is really strong.

#958

**Skin intraneural phosphorylated α-synuclein is a highly specific biomarker for early Parkinson’s disease **
“In contrast, olfactory function, although more impaired in PD than in non-PD patients, only seems to have a more limited diagnostic accuracy.”

Certainly in my case. I have a highly reduced sense of smell, and I don’t have PD.

https://academic.oup.com/brain/advance-article-abstract/doi/10.1093/brain/awaf313/8249109?redirectedFrom=fulltext&login=false

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#959

Tried this? I’ve heard good things about this

#960

Have not tried this.

I’ve tried several other nootropics but none of them did enough to justify the cost/benefit ratio.

#961

Forgot to cross post here, SGLT2i seem like a no-brainer for people at risk of PD: Canagliflozin - Another Top Longevity Drug - #1847 by adssx

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#962

Turkish preprint: Personalized Metabolite Biomarker Predictions Reveal Heterogeneous Characteristics of Parkinson’s Disease 2025

Furthermore, certain metabolites such as melatonin, sphingosine, and biliverdin, though not identified by the general approach, showed distinct secretion patterns across patient clusters. For instance, an undersecretion pattern of melatonin, possibly associated with the sleep disturbance symptom of PD, was detected exclusively in one subgroup.
While certain metabolites like melatonin, prostaglandins, sphingosine, biliverdin, tyramine, and betaine etc., which are associated with PD or neurodegeneration, were not predicted as potential biomarkers in the classical approach, they demonstrated group-specific patterns in the cluster-based approach.
For instance, melatonin, 6-hydroxymelatonin, and L-iduronic acid exhibit an undersecretion pattern in cluster C3, while no clear trend is observed in clusters C1 and C2.

@John_Hemming: they looked at serum and not CSF I guess, still, there might be people with PD who benefit more from melatonin supplementation than others.

#963

I think the nub of the issue is neurodegeneration which results from damage to the mitochondria. That could have many causes and the symptoms will still be the same. Once things get beyond a certain limit the mitophagy fails.

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#964