#462

Thanks @tj_long @Pat25!

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#463

Manganese and biotin re: Parkinson’s?

Excess manganese can be toxic with Parkinson’s symptoms. Biotin to the rescue.

Biotin mitigates the development of manganese-induced, Parkinson’s disease–related neurotoxicity in Drosophila and human neurons

https://www.science.org/doi/10.1126/scisignal.adn9868

Don’t know if this is relevant, but just in case.

#464

Hum… Biotin was also highlighted in this paper (together with riboflavin): Meta-analysis of shotgun sequencing of gut microbiota in Parkinson’s disease 2024

#465

But at what dose, biotin? Anyhow, can’t one simply test for manganese levels? Instead, maybe there is some flaw in manganese metabolism in PD folks that biotin fixes, then you don’t even need excess manganese to trigger the pathology. Just brainstorming - might be interesting to look at how manganese is handled physiologically, to see where a potential problem might arise.

#466

I tested my hair manganese, and it was normal. Animal models of PD are wea; the disease is often triggered by giving the animal a single toxic agent (e.g., a pesticide such as paraquat). But humans rarely get the disease like that. So, biotin might work in humans with Manganese-induced PD (if that ever exists) but not others.

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#467

If PD is a subset of mitochondrial diseases then it is quite possible for PD to be triggered by lots of things, but for those things to actually be nothing to do with PD in humans. Hence any conclusions from those models may not actually mean that much in terms of human beings.

#468

Two essential papers to me:

Modeling Parkinson’s disease pathology in human dopaminergic neurons by sequential exposure to α-synuclein fibrils and proinflammatory cytokines 2024
Explained here: “Lewy bodies form in dopaminergic neurons only when immune response and alpha-synuclein buildup co-occur.”

Lewy bodies (LBs), α-synuclein-enriched intracellular inclusions, are a hallmark of Parkinson’s disease (PD) pathology, yet a cellular model for LB formation remains elusive. Recent evidence indicates that immune dysfunction may contribute to the development of PD. In this study, we found that induced pluripotent stem cell (iPSC)-derived human dopaminergic (DA) neurons form LB-like inclusions after treatment with α-synuclein preformed fibrils (PFFs) but only when coupled to a model of immune challenge (interferon-γ or interleukin-1β treatment) or when co-cultured with activated microglia-like cells. Exposure to interferon-γ impairs lysosome function in DA neurons, contributing to LB formation. The knockdown of LAMP2 or the knockout of GBA in conjunction with PFF administration is sufficient for inclusion formation. Finally, we observed that the LB-like inclusions in iPSC-derived DA neurons are membrane bound, suggesting that they are not limited to the cytoplasmic compartment but may be formed due to dysfunctions in autophagy. Together, these data indicate that immune-triggered lysosomal dysfunction may contribute to the development of PD pathology.

Also, they found that the Lewy body-like inclusions is prevented by treating the cells with the NRF2 activator Perillaldehyde.

Systemic inflammation accelerates neurodegeneration in a rat model of Parkinson’s disease overexpressing human alpha synuclein 2024
Inflammation alone makes the neurons “dormant” (see also here), so potentially they could be “reactivated”, but you need inflammation + alpha-synuclein to kill the neurons.

Both papers support the “dual-hit” hypothesis: α-Synuclein Aggregation + Neuroinflammation => Neuronal death + Lewy bodies.

If correct, then to “cure” PD, you’d need:

  1. Lower inflammation and immune dysregulation in the brain: NLRP3 inhibitors (dapansutrile) + Brain-penetrant immunosuppressant (everolimus, azathioprine)? Ibuprofen?
  2. Enhance autophagy and lysosomal function in the brain: brain-penetrant mTOR inhibitor (*rolimus? urolithin A?) + lysosomal enhancers (ambroxol)?
  3. Restart neurogenesis (intermittent hypoxia? nicotinamide riboside? stem cell therapy?)

Most RCTs focus only on one of the above strategies and achieve nothing. I don’t see how you could cure such a complex disease with a single wonder drug. Thankfully, this year, we should have the results of the following trials:

  • Azathioprine (AZA-PD)
  • Ambroxol 5x (AMBALS, AMBITIOUS, Agyany, ANeED, GREAT)
  • Intermittent hypoxia (TALISMAN-2)
  • Nicotinamide riboside (NOPARK)

I doubt one of them will “work” alone. But I think/hope they will all hint at some benefits along one of the above axes (neuroinflammation, neurotoxic protein clearance, and/or neurogenesis). Then, similar to HIV, you could have single-pill combinations of 3 agents (“triple therapy”).

Another issue is that one drug might help with something but deteriorate something else. For instance, rapamycin might help to enhance mitophagy, but it might also increase glucose levels and create more inflammation in people with PD, resulting in a net negative (theoretically).

Anyway, just my two cents here…

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#469

Which is why it might make sense to combine it with glucose lowering agents. I think your intuition is absolutely correct - it will take a combination of interventions to hit PD, furthermore, because PD is so heterogenous, it might take different combinations depending on the individual patient.

We can divide this into two parts. One is the triggering etiology, and the other into repair of the damage, similar to prevention vs cure. If the original insult is limited to the inciting incident, then all you are addressing are the downstream effects, like in the example where a drug destroyed substantia nigra leading to a PD presentation. What can you do about etiology here other than stopping the damaging drug, focus on recovery. But when PD is a progressive disease, with an underlying pathology, you must focus on addressing that too, otherwise you’re just addressing symptoms, like focusing just on dopamine. So, if say, pesticides cause PD, then how does this PD progress? Presumably, you have exposure, then the exposure stops - so why should PD keep progressing after the exposure stops? But if there is some other underlying pathology that keeps the PD getting worse over time, I guess that’s the target. Circling back to the original issue - what exactly causes PD, and what caused your particular PD, that might determine how to address it. And to gain clues as to the cause, one should at least keep vigilant track of as many relevant biomarkers and symptoms as possible, and based on that try to figure out the particular presentation that might indicate where exactly is the problem and how to tackle it.

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#470

My only concern with this is that PD might be caused by (or cause) insulin resistance (or glycemic dysregulation) in the brain, and not necessarily in the rest of the body. So compound A (let’s say rapa) might dysregulate brain glucose, and you wouldn’t know by looking at your serum glucose levels. You could add a glucose-lowering agent to normalize your serum levels but this might not affect your brain levels.

Unfortunately, science has been slow in subtyping PD patients in meaningful ways. However, recently, two subtypes emerged:

That’s the billion dollar question, unanswered for 200 years…

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#471

How would glycemic dysregulation be limited to the brain?

#472

I’m not sure anyone really knows. See: Insulin Resistance in Peripheral Tissues and the Brain: A Tale of Two Sites 2022

This has led to the investigation of brain or central nervous system (CNS) insulin resistance and the question of the relation between CNS and peripheral insulin resistance. While both may involve dysregulated insulin signaling, the two conditions are not identical and not always interlinked.
Often, the tissue selectivity ultimately leads to widespread tissue insulin resistance in the periphery. While this can sometimes extend to the CNS, it is not always the case as discussed above. It will be important to continue exploring this area to determine why peripheral insulin resistance does not always lead to CNS insulin resistance, as it can spread from tissue to tissue in the periphery. This could be related to the role of the BBB in mediating CNS insulin levels or, hypothetically, the ability of the CNS to regulate its own insulin levels

State of the Science on Brain Insulin Resistance and Cognitive Decline Due to Alzheimer’s Disease 2024

Type 2 diabetes mellitus (T2DM) is common and increasing in prevalence worldwide, with devastating public health consequences. While peripheral insulin resistance is a key feature of most forms of T2DM and has been investigated for over a century, research on brain insulin resistance (BIR) has more recently been developed, including in the context of T2DM and non-diabetes states. Recent data support the presence of BIR in the aging brain, even in non-diabetes states, and found that BIR may be a feature in Alzheimer’s disease (AD) and contributes to cognitive impairment. Further, therapies used to treat T2DM are now being investigated in the context of AD treatment and prevention, including insulin. In this review, we offer a definition of BIR, and present evidence for BIR in AD; we discuss the expression, function, and activation of the insulin receptor (INSR) in the brain; how BIR could develop; tools to study BIR; how BIR correlates with current AD hallmarks; and regional/cellular involvement of BIR. We close with a discussion on resilience to both BIR and AD, how current tools can be improved to better understand BIR, and future avenues for research. Overall, this review and position paper highlights BIR as a plausible therapeutic target for the prevention of cognitive decline and dementia due to AD.

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#473

Lets not forget this Finish study that showed that 90% of PD patients carry a specific strain of gut bacteria : Researchers discover a potential cause of Parkinson’s disease | University of Helsinki. The hypothesis is that this (unkown) strain of Desulfovibrio generates a toxin that migrates to the brain via the Vagus Nerve.

Accordingly, a strong antibiotics course that can eradicate all Desulfovibrio strains in the gut, followed by repopulating the gut with high dose pro-biotics (to prevent recolonization with Desulfovibrio) should stop further progression of PD in its tracks (though this will not reverse any brain damage that already exists). Might want to check if your water supply has Desulfovibrio (this can happen with well water): these strains of bacteria will often cause a faint smell of rotten eggs when you run your cold water line.

Checking for leaky gut syndrome might also help : With a healthy gut lining, any toxins produced by Desulfovibrio should not make it to the Vagus Nerve in the first place and just be absorbed by blood vessels and detoxified by the liver first-pass metabolism.

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#474

It’s a weak paper based on a worm model of Parkinson’s disease. It was published 2 years ago and has not been replicated since then as far as I know. If the authors were convinced by their own paper they would have published a new one in mice by now. So I’m fairly skeptical.

Still, there’s a case for antibiotics and some are seriously being studied.

Also, I did a microbiome test with Zoe and it came out as perfectly healthy.

But it could be worth checking for a leaky gut (although what are the interventions then?).

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#475

I’m jealous of your ZOE results!

Grant had me do the KBMO gut barrier panel. It was fairly simple, so perhaps that would be of interest to you.

He could of course give you a much better answer, but my guess from the report is if the result wasn’t good, you would eliminate the foods that cause your inflammation. Those foods are also in the report. My report showed almost nothing, so it’s still a mystery why my ZOE results were so poor. Happy to send you my results if you’d like to see what it looks like.

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#476

On the Role of Store-Operated Calcium Entry in Acute and Chronic Neurodegenerative Diseases

“However, the dysregulation of ER Ca2+ homeostasis is one of the mechanisms affecting the selective loss of DA neurons of the substantia nigra pars compacta(Stefani et al., 2012; Calì et al., 2014). Unlike other neurons, rhythmic activity of DA neurons depends on L-type Cav1.3 channels. Pharmacological inhibition of these currents by izradipine restores Ca2+−independent “juvenile” pacemaking activity and protects DA neurons in animal models of the disease (Chan et al., 2007). In normal conditions, the pacemaking activity of DA neurons is inhibited by the TRPC1-STIM1 complex. Accordingly, increased L-type Cav1.3 currents were observed upon Stim1 or TRPC1 silencing. Interestingly, the neurotoxin 1-methyl-4-phenylpyridinium ion (MPP+)—that mimics PD—decreases the level of TRPC1 and its interaction with STIM1, thus increasing neuronal death both in vitro and in vivo (Bollimuntha et al., 2005; Selvaraj et al., 2012). Molecularly, the decrease of TRPC1 expression leads to an abnormal increase in Cav1.3 activity, thereby causing degeneration of DA neurons (Sun et al., 2017; Figure 2). Despite the abnormal increase in L-type activity, downregulation of TRPC1 also leads to the loss of SOCE, thus triggering ER stress and initiation of the unfolded protein response (UPR) in DA neurons (Selvaraj et al., 2012). Conversely, in PC12 cell lines, Stim1 knockdown significantly attenuated 6-hydroxydopamine (6-OHDA)- and MPP±induced toxicity through inhibition of SOCE-mediated Ca2±overload (Li et al., 2013, 2014); while, pharmacological inhibition of SOCE by SKF-96365 was protective against MPP+ cytotoxicity (Chen et al., 2013). The effect on SOCE was related to Orai1 and L-type Ca2+ channels, but not to TRPC1 (Li et al., 2014). Moreover, Stim1 knockdown attenuated 6-OHDA- and MMP±induced mitochondrial Ca2+ uptake and dysfunction in PC12 cells (Li et al., 2013, 2014). This further underscores that STIM1, through SOCE, may be responsible for neuronal oxidative stress induced by ER stress and mitochondrial dysfunction in PD.

In support of the important role of SOCE for DA neurons survival, the mutant dominant-negative form of Orai1 channel leads to tyrosine hydroxylase downregulation in Drosophila thus affecting dopamine synthesis and release (Pathak et al., 2015). Furthermore, skin fibroblasts from idiopathic PD patients and patients bearing familial R747W mutation in PLA2g6 gene, that encodes for a Ca2± independent phospholipase A2, exhibit depleted stores and reduced SOCE (Zhou et al., 2016). Overall, these findings indicate that SOCE pathway in DA neurons represents an attractive target for PD drug discovery (Pchitskaya et al., 2018).”

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#477

Failed: Inhibikase hits pause on Parkinson’s program over efficacy as it prioritizes lung drug

#478

I mentioned this drug last week. They’ve just published their results in MSA, this is HUGE: Alterity Therapeutics Announces Positive ATH434 Phase 2 Trial Results in Multiple System Atrophy Led By Robust Clinical Efficacy

The topline data showed that ATH434 produced clinically and statistically significant improvement on the modified UMSARS Part I, a functional rating scale that assesses disability on activities of daily living affected in MSA1. On this important clinical measure, ATH434 demonstrated 48% slowing of clinical progression at the 50 mg dose (p=0.03)^ and 29% slowing of clinical progression at the 75 mg dose (p=0.2) at Week 52 when compared with placebo.

MSA is a very aggressive form of Parkinson’s disease. People die in a few years post-diagnosis. The drug works in the macaque model of PD. That’s very promising.

Markets seem positively surprised:

image
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#479

Polystyrene Nanoplastics Hitch-Hike the Gut–Brain Axis to Exacerbate Parkinson’s Pathology 2025

Abstract Image

Pollution, pesticides, chemicals, and now nanoplastics, PD is really the disease of the modern world :slight_smile:

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#480

Yes, but that further strengthens my view that while many of these might exacerbate or even perhaps trigger the initiation of the PD pathology, there are other more crucial factors that make this disease possible. In some ways I worry that focusing on pesticides, microplastics, the gut axis etc. distracts from the core underlying pathology. PD existed long before plastics, pesticides etc. were introduced. As I read more about PD, I (personally) am trying to focus more on the endogenous biological processes, such as disregulation of calcium signalling pathways. Of course, there may be downstream interaction between exogenous toxic agents, but exposure to toxins is wider than PD prevalence, so I feel the core pathology is where research should concentrate, seems to me😥.

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#481

PD appeared during the Industrial Revolution. It’s unclear whether it existed before.

But yes, we should know the underlying dysfunctional processes. Unfortunately, there are many (dozens?) of processes that are dysfunctional and it’s hard to know which one “started”. The successful ATH434 trial in MSA suggests that iron dysregulation is very important: https://alteritytherapeutics.com/wp-content/uploads/-97 There aren’t many successful phase 2 trials in PD/MSA/DLB, even less so for potentially disease-modifying treatments. So this is really big. Unfortunately, before ATH434 becomes commercially available, I don’t think we have ways to “fix” brain iron…

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