Parkinson's disease

#737

Nope sorry

This Northwestern U team found a potential mechanism of action for NALL (Tanganil derivative): N-acetyl-l-leucine lowers pS129-synuclein and improves synaptic function in models of Parkinson’s disease

It’s a preprint but very interesting.

N-acetyl-L-leucine (NALL), a derivative of the branched-chain amino acid leucine, has shown therapeutic potential in neurodegenerative diseases, including in prodromal stages of Parkinson’s disease (PD). However, the mechanism of its protective effects has been largely unknown. Using discovery-based proteomics, we found that treatment with NALL led to upregulation of lysosomal, mitochondrial, and synaptic proteins in PD patient-derived dopaminergic neurons. NALL reduced levels of pathological pS129-alpha-synuclein in dopaminergic neurons from patients harboring GBA1 or LRRK2 mutations. This decrease in pS129-syn was dependent on serine protease HTRA1 that was induced by NALL treatment of dopaminergic neurons. NALL also upregulated expression of wild-type parkin in both GBA1 and LRRK2 mutant neurons, leading to an increase in functional dopamine transporter and synaptic membrane-associated synaptojanin-1, suggesting improved synaptic function. Furthermore, NALL treatment of mutant LRRK2R1441C knock-in mice led to decreased pS129-alpha-synuclein, increased parkin and improved dopamine-dependent motor learning deficits. These findings highlight the therapeutic potential of NALL in PD by its protective effects on α-synuclein pathology and synaptic function in vulnerable dopaminergic neurons.

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#738

That’s funny, because thanks to your post recommendation of some weeks ago, I found this (I suffer from RLS):

Acetyl-DL-leucine improves restless legs syndrome: a case report

And also couldn’t access it.

Some of the same authors (not all):

Treatment of restless legs syndrome with acetyl-DL-leucine – accidental findings and a small case series.

https://www.researchgate.net/publication/350343306_Treatment_of_restless_legs_syndrome_with_acetyl-DL-leucine_-_accidental_findings_and_a_small_case_series

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#739

I looked through the October 2024 posts in this thread, but didn’t see this, I apologize if this is a repeat:

Effects of antimicrobial exposure on the risk of Parkinson’s disease

https://www.prd-journal.com/article/S1353-8020(24)01093-9/fulltext

“PD risk was lower among adults who received penicillins and higher among those exposed to antifungal medicines.”

My point here being, that isn’t rapamycin considered an antifungal at least in some contexts? I know some users (RapAdmin) claim it has gotten rid of their persistent toenail fungus. Or perhaps the specific classes of antifungal medication that affect the gut microbiome is in question.

We do know that rapamycin affects the composition of the gut microbiome.

Rapamycin Immunomodulation Utilizes Time-Dependent Alterations of Lymph Node Architecture, Leukocyte Trafficking, and Gut Microbiome

Of course there’s the literature about rapamycin and PD, but perhaps some pleiotropic effects, negative and positive also mediated through the gut microbiome.

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#740

Intact microdissection of stellate ganglia in a Parkinson’s disease model reveals aggregation of mutant human α-synuclein in their cell bodies

https://physoc.onlinelibrary.wiley.com/doi/10.1113/EP092261

So re: PD pathology in the heart. What drugs can address that?

“ Importantly, cardiovascular diseases have been increasingly recognised as a key non-motor feature of PD (Lee et al., 2023; Scorza et al., 2018). Arrhythmia and sympathetic denervation are considered as cardiac features of PD (Jain & Goldstein, 2012; Nishida et al., 2017). Cardiac autonomic dysregulation in PD is thought to play a pivotal role in understanding PD (Lee et al., 2023). Earlier research demonstrated that PD patients present with a reduction in the tyrosine hydroxylase (TH)-positive sympathetic neurons in the heart (Amino et al., 2005; Takahashi et al., 2015), and recent findings have established PD-associated pathology, such as Lewy bodies (LBs), in the heart (Javanshiri et al., 2022).”

#741

There are ongoing trials of terazosin and carvedilol, aiming to reverse cardiac sympathetic denervation.

The role of beta-blockers is also controversial. Some think it might help, others (I am one of them) think that they make things worse.

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#742
#743

Pre-symptomatic Parkinson’s disease blood test quantifying repetitive sequence motifs in transfer RNA fragments 2025

Early, efficient Parkinson’s disease (PD) tests may facilitate pre-symptomatic diagnosis and disease-modifying therapies. Here we report elevated levels of PD-specific transfer RNA fragments carrying a conserved sequence motif (RGTTCRA-tRFs) in the substantia nigra, cerebrospinal fluid and blood of patients with PD. A whole blood qPCR test detecting elevated RGTTCRA-tRFs and reduced mitochondrial-originated tRFs (MT-tRFs) segregated pre-symptomatic patients with PD from controls (area under the receiver operating characteristic curve (ROC-AUC) of 0.75 versus 0.71 based on traditional clinical scoring). Strengthening PD relevance, patients carrying PD-related mutations presented higher blood RGTTCRA-tRFs/MT-tRFs ratios than mutation-carrying non-symptomatic controls, and RGTTCRA-tRF levels decreased in patients’ blood after deep brain stimulation. Furthermore, RGTTCRA-tRFs complementarity to ribosomal RNA and the translation-supporting LeuCAG3-tRF might aggravate PD via translational inhibition, as reflected by disrupted ribosomal association of RGTTCRA-tRFs in depolarized neuroblastoma cells. Our findings show tRF involvement in PD and suggest a potential simple and safe blood test that may aid clinicians in pre-symptomatic PD diagnosis after validation in larger independent cohorts.

Transfer RNA fragments (tRFs) are 16–50 nucleotide (nt)-long, non-coding RNAs originating from multiple nuclear or mitochondrial transfer RNA (tRNA) genes. Several enzymes cleave tRNAs to yield tRFs: angiogenin (Ang) generates 5′-half and 3′-half tRFs, whereas Ang, Dicer and other nucleases yield 5′-tRFs, i-tRFs and 3′-tRFs26. Because tRFs harbor repetitive sequence motifs inherited from their parental tRNAs, changes can be detected in an entire family of closely related transcripts, albeit of different origins and types, produced by different endonucleases, and originating from either nuclear or mitochondrial genomes. Correspondingly, tRFs may reflect transcriptional changes or malfunctions in both the nucleus and the mitochondria, whose DNA is known to be damaged in PD. Intriguingly, altered Ang levels, Ang mutations and Ang-produced tRFs may exert both PD-protective and cytotoxic roles. Furthermore, blood cell tRF levels present diagnostic value in various diseases, including ischemic stroke, amyotrophic lateral sclerosis, epilepsy and cellular or organismal stress. Accordingly, tRFs emerge as the perfect candidates for a blood-based PD biomarker.

Press: RNA-based blood test identifies Parkinson’s before symptoms appear

@John_Hemming

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#744

What people miss is when the mtDNA is damaged this results in splicing and other transcriptional changes. That causes the phenotype of aging/parkinsons. The reason this is more obvious in parkinsons in the substantia nigra is because of its proximity to the third ventricle.

1 Like
#745

I had not heard of this before:

Age and genetic predisposition play a role. But Bloem and the wider neurological community contend that those two factors alone cannot explain the steep rise in cases. In a 2024 paper co-authored with U.S. neurologist Ray Dorsey, Bloem wrote that Parkinson’s is “predominantly an environmental disease” — a condition shaped less by genetics and more by prolonged exposure to toxicants like air pollution, industrial solvents and, above all, pesticides.

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#746

And some good news:

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#747

Most know that paraquat is a dangerous chemical. I’ve been told several times. We don’t use it, though I’ve seen it and can get it. Most herbicide is pretty safe. Roundup has a lot of talk about causing cancer and there have been court cases won which is now breaking Bayer. Some may celebrate, but the chemicals needed to replace it will be worse. Roundup is tightly bound to the surface of the soil and broken down. It never enters the ground water. A good feature.

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#748

Just read about this new medication - treatment.
The once-daily pill, tavapadon.

Link: New Parkinson's medication alleviates symptoms without common side effects | Fox News

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#749

Bloem is very vocal on PD being an environmental disease (see: Parkinson's disease - #531 by adssx ). He’s also leading the trials of hypoxia in PD. He seems very good.

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#750

Multicomponent Mendelian randomization and machine learning studies of potential drug targets for neurodegenerative diseases 2025

:warning: Chinese preprint :warning:

Neurodegenerative diseases (NDDs) remain a global health challenge. Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the main types of NDDs worldwide, and Mendelian Randomization (MR) analysis across multi-omics and the entire genome offers novel strategies for identifying potential drug targets. This study used MR and summary-based MR(SMR) analysis to explore the causal relationship between genes and NDDs. Colocalization analysis and machine learning further validated and reinforced the MR findings. The pharmacological activity of candidate drug targets was confirmed via molecular docking and Molecular dynamics. This study revealed 14 genes that were closely associated with both NDDs. Specifically, IQCE(AD), HDHD2(AD), COMMD10(AD), ALPP (AD), FXYD6 (AD), STK3 (PD), LHFPL2 (PD), and ENPP4 (PD) were identified as risk factors for NDDs (OR > 1), whereas HEXIM2 (AD), TSC22D4 (AD), CHRNB1 (PD), BAG4 (PD), SLC25A1 (PD), and IL15 (PD) were protective factors (OR < 1). Molecular docking results revealed strong binding activities for PREDNISOLONE(ALPP = -7.6 kcal/mol), PANCURONIUM BROMIDE(CHRNB1 = -8 kcal/mol), CHEMBL379975(STK3 =-10.7 kcal/mol) and SIROLIMUS(IL15 = -9 kcal/mol). Molecular dynamics simulations confirmed the stable binding of the IL15-Sirolimus, ALPP-Prednisolone, STK3-CHEMBL379975, and CHRNB1-Rocuronium bromide complexes. This multi-omics study revealed 14 promising therapeutic targets for NDDs, providing new insights for targeted therapies and clinical strategies for NDDs. Our results provide evidence for future studies aimed at developing appropriate therapeutic interventions.
Molecular docking indicates that PREDNISOLONE (ALPP), PANCURONIUM BROMIDE (CHRNB1), CHEMBL379975 (STK3), and SIROLIMUS (IL15) are the most viable drug candidates for the treatment of both NDDs (Supplementary Table S13). Molecular dynamics simulations confirmed the stable binding of the IL15–Sirolimus, ALPP–Prednisolone, STK3–CHEMBL379975, and CHRNB1–Rocuronium bromide complexes.
Studies in PD patients have shown that Parkin and NIX support the formation of memory T cells by being upregulated in response to interleukin 15 (IL-15). IL-15, a cytokine involved in the survival and differentiation of T cells, stimulates the expression of Parkin and NIX, which are essential for maintaining mitochondrial integrity and regulating cellular energy. The upregulation of these proteins facilitates the metabolic and functional adaptations required for the generation and persistence of memory T cells, which are crucial for the adaptive immune response. Significant alterations in IL-15 have been observed in both the substantia nigra and striatum of patients with clinical PD32-35. The MR analysis indicates a protective role of IL15 in PD progression, consistent with foundational research outcomes. The IL-15-targeting drug LEVODOPA has been clinically approved for PD treatment. Molecular docking results suggest that SIROLIMUS may exhibit stronger ligand-protein binding compared to LEVODOPA (Supplementary Table S11, S13). The inhibition of mTOR activity by SIROLIMUS leads to autophagy activation. In a model of synucleinopathy, SIROLIMUS decreased α-synuclein accumulation, indicating that sirolimus treatment could prevent α-synuclein-induced neurodegeneration36. Through the Hippo pathway’s Mst1/2 (STK3/STK4), STK3 modulates autophagy under mitochondrial stress, maintaining mitochondrial stability and cellular integrity. In PD models, reduced Mst1 (STK3) expression helps mitigate the loss of TH-positive neurons, improving behavioral deficits and mitochondrial function37, further supporting its identification as a PD risk factor. CHEMBL379975 demonstrates the most optimal binding mode for targeting STK3 (Supplementary Table S11,S13). ALPP functions as a positive regulator of placental growth and is involved in essential cellular processes, including protein phosphorylation, cell growth, apoptosis, and migration during embryonic development. While no studies have yet established a direct association between ALPP and AD, it has been linked to increased disease risk. PREDNISOLONE treatment improves amyloid-beta (Aβ)-induced cognitive deficits in AD mice and inhibits microglial activation in the cortex and hippocampus. RNA sequencing analysis revealed that PREDNISOLONE ultimately salvages cognitive dysfunction by improving synaptic function and inhibiting immune and inflammatory processes38. PREDNISOLONE, which exhibits the strongest molecular affinity for ALPP, demonstrates significant therapeutic potential but requires further validation through fundamental research. CHRNB1 encodes the β subunit of the acetylcholine receptor at the neuromuscular junction, with mutations in this gene linked to congenital myasthenic syndrome (CMS)39,40. A potential relationship exists between CHRNB1 and tremor symptoms in PD, and our findings indicate a negative correlation with PD risk. Despite strong colocalization evidence, the precise mechanisms through which CHRNB1 mitigates PD risk remain to be determined. Among potential drugs, PANCURONIUM BROMIDE shows the highest promise for targeting CHRNB1 (Supplementary Table S11,S13).

Citrate also gets a mention @John_Hemming:

FXYD6 mRNA is essential for dendritic localization, and the loss of this localization is associated with impaired Na+/K±ATPase (NKA) function in dendrites, while NKA function in somatic cells remains unaffected. Additionally, FXYD6 expression is decreased in the brains of Tg2576 mice and human hippocampal tissues, suggesting that reduced FXYD6 expression may be detrimental to neurons. The dysfunction of Na+/K±ATPase due to low FXYD6 expression may lead to disrupted calcium balance, contributing to neurodegeneration by disturbing calcium homeostasis in NDDs48,49. LHFPL2 protein is abundantly expressed in malignant brain tissues and may play a role in linking cancer and PD genetically, potentially through interactions with TPM1. Short-term LPS treatment results in the downregulation of several genes associated with immune cell differentiation, including LHFPL2, suggesting a potential role for LHFPL2 in immune regulation and its involvement in the pathophysiology of NDDs like PD50. BAG4 functions as a negative regulator of Parkin translocation and works in concert with HSPA1L to regulate Parkin’s localization following mitochondrial damage in HeLa cells. Knockdown of HSPA1L significantly reduces Parkin translocation (P < 0.01), while knockdown of BAG4 enhances Parkin translocation, specifically in a PINK1-dependent manner, promoting Parkin’s relocation to damaged mitochondria51. Currently, research on the relationship between ENPP4 and PD is limited. ENPP4 and the PD-related gene PARK2 are located in the same chromosomal region, sparking interest in their potential association. However, existing studies have primarily focused on changes in gene expression and metabolic pathways, without investigating the specific role of ENPP4 in the pathogenesis of PD52. SLC25A1, a mitochondrial membrane transporter, is crucial for mitochondrial function regulation. Its expression is influenced by SUCLG1, which enhances mitochondrial mass and may increase SLC25A1 levels. Metabolite assays show a correlation between SLC25A1 expression and increased CA expression. In cells overexpressing SUCLG1, the addition of an SLC25A1 inhibitor partially restores PNF cell function, indicating that SUCLG1 affects PNF cell development through SLC25A1. In mice, abnormal SLC25A1 expression disrupts citrate/acetyl-CoA homeostasis, damages white matter integrity, and alters synaptic plasticity and morphology, potentially contributing to ASD-like phenotypes and proteomic changes. Our study identified IQCE, HDHD2, COMMD10, and FXYD6 as risk factors for AD, while HEXIM1 and TSC22D4 were associated with a reduced risk of AD. BAG4 and SLC25A1 were identified as protective factors for PD, while ENPP4 and LHFPL2 were linked to increased PD risk. However, the mechanisms through which these QTLs influence the two NDDs remain unclear and require further investigation.

Among these, PREDNISOLONE was identified as the most promising targeted drug for treating AD via ALPP, while PANCURONIUM BROMIDE, CHEMBL379975, and SIROLIMUS showed the highest potential for treating PD via CHRNB1, STK3, and IL15, respectively.

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#751

Its just the citrate carrier. This is important, but not as important at membrane potential.

#752

So, another possible use of rapamycin! Unfortunately the PD data in transplant patients is a mixed bag, not very positive:

Reduced Prevalence of Parkinson’s Disease in Patients Prescribed Calcineurin Inhibitors

“Patients prescribed CNIs have decreased odds of PD diagnosis compared to the general population-like control, while patients prescribed SIR do not. Notably, patients prescribed TAC have a decreased prevalence of PD compared to patients prescribed SIR or CySp.

Conclusions:

Our results suggest CNIs, especially those acting within the brain, may prevent PD. The reduced prevalence of PD in patients prescribed TAC, compared to patients prescribed SIR, suggests that mechanisms of calcineurin inhibition— other than immunosuppression, which is common to both drugs— are driving the reduction. Therefore, CNIs may provide a promising therapeutic approach for PD.”

#753

Some other papers are more positive: Parkinson's disease - #413 by adssx

An the paper you cited, the interesting part that caught my mind was:

While immunosuppression likely contributes to reducing the prevalence of PD, TAC’s additional effects, as previously discussed, make it a more potent preventative agent. It is also worth noting that while both SIR and TAC act as autophagy inducers, SIR only initiates autophagy. In contrast, TAC not only initiates but also sustains autophagy, likely enhancing its potential role in modulating PD risk. This difference is crucial, as excessive induction of autophagy without efficient lysosomal degradation can lead to cell death, rather than promoting clearance of misfolded proteins.

#754

Yes, that is notable. Interesting direction to pursue further. Btw. I wonder how this fits into the debate about whether rapamycin crosses the BBB.

#755

Rapamycin does not cross the BBB. But it might not need to: Parkinson's disease - #730 by adssx

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#756

The accelerated brain aging here would be less targeted on the substantia nigra.