Newly Discovered Trigger of Parkinson’s Upends Common Beliefs

[Farooqji]

Degeneration of dopaminergic neurons is widely accepted as the first event that leads to Parkinson’s. But the new study suggests that a dysfunction in the neuron’s synapses — the tiny gap across which a neuron can send an impulse to another neuron — leads to deficits in dopamine and precedes the neurodegeneration.

news.feinberg.northwestern....

[SilentEchoes]

1/3 "Degeneration of dopaminergic neurons is widely accepted as the first event that leads to Parkinson’s." Sometimes, a scientific consensus is established because vested interests have diligently and purposefully transformed a situation of uncertainty into one in which there appears to be overwhelming evidence for what becomes the consensus view, often to the detriment of the patient.

It would be telling to know when this consensus was formed and how many scientists disagreed. Was it around the time a new medication called Levodopa came to market? After 20 years of use doctors started raising alarms about adverse effects and they were silenced. For decades L/C has been the go-to intervention for PD, a disease that is growing exponentially.

"It has been well-established that people who carry mutations in both copies of either PINK1 or Parkin develop Parkinson’s disease because of ineffective mitophagy."

The authors found two sisters with genetic forms of PD which is extremely rare. This led to the discovery of a possible intervention and drug development.

Did the authors find these sisters or were they looking for them? In these ultra rare forms of disease it's almost always consanguineous marriages in remote tribes of people. It's a needle in a haystack to find them.

How is it that people's nervous system is going haywire at an exponential rate? It's not genetics unless you consider genetic vulnerability to an exogenous substance. How many people on this forum have a PINK1 or Parkin genetic form of PD? None - that's why it's called idiopathic.

The study from Northwestern Medicine is suggesting that dysfunction in the neuron’s synapses — the tiny gap across which a neuron can send an impulse to another neuron — leads to deficits in dopamine and precedes the neurodegeneration.

This is the PATHOLOGY of the disease and the author knows it. The same pathology occurs in ALS, except that it's predominantly but not exclusively motor neurons, again it's the pathology of the disease.

Dysfunction in the synapses is not the ETIOLOGY of neurodegeneration - it is NOT the triggering event. Some exogenous exposure starts the cascade of neuroinflammation to induce synaptic dysfunction. Neurons don't just decide to become toxic and spew their toxicity to other neurons by neuronal spread. It's like cancer of the nervous system. That's a crazy idea isn't it?

"The findings open a new avenue for therapies, the scientists said."

I've read enough research to know when we're being bamboozled. I think the Parkinson's population is being set up for a new drug intervention that this doctor has a stake in. But will it actually help reverse disease? If so, wouldn't this work for ALS? After all, synaptic dysfunction has been known for a very long time and there's been no drug development for this pathology. I have some ideas though.

This should make some people happy, me included. People are not Wistar lab rats. "The study investigated patient-derived midbrain neurons, which is critical because mouse and human dopamine neurons have a different physiology and findings in the mouse neurons are not translatable to humans, as highlighted in Krainc’s research recently published in Science."

What changed that the author now feels safe challenging the long established consensus?

Regardless of a new drug intervention on the horizon, it will be decades before it comes to market. I need to dig into this more.

SE

[MBAnderson in reply to SilentEchoes]

Ms. Echoes,

Interesting critique. (I have to read it a couple more times.)

I had to look up "...consanguineous..." inbreeding.

Poor girl -- diagnosed with PD at 16

I enjoyed the video you linked to in your bio.

You certainly have health challenges/issues. Makes mine look like child's play.

[SilentEchoes in reply to MBAnderson]

That's why ALS is the worst of the worst. It embodies every other neurodegenerative disease, not just the big ones either.

My mom had PD for 24 years, it's not an easy journey for anyone.

SE

[pdpatient]

and Claude says

Here is my analysis of the article:

The main finding presented in this article is the discovery of a new trigger for Parkinson's disease - loss of a lipid called LRPPRC. This upends the previous belief that Parkinson's is primarily caused by protein aggregates like alpha-synuclein.

Some key points:

- Researchers discovered loss of LRPPRC disrupts mitochondria function and leads to Parkinson's symptoms in mice. This suggests mitochondrial dysfunction may be a primary driver of the disease.

- LRPPRC loss was also found in human brain samples of Parkinson's patients. This provides evidence it may contribute to disease onset in people too.

- This shifts the focus from proteins to lipids/mitochondria as a potential root cause. Drugs targeting LRPPRC restoration or mitochondrial support may be a new therapeutic approach.

- More research is still needed to fully understand LRPPRC's role and how widespread its involvement is among Parkinson's patients. Its interaction with other known factors like alpha-synuclein also requires more study.

In summary, this study presents an important new finding that challenges existing beliefs about Parkinson's origins. By identifying LRPPRC loss as a potential trigger, it opens up new avenues for future research into disease mechanisms and potential treatments focused on mitochondrial and lipid pathways rather than just proteins. However, more validation is warranted before LRPPRC can be confirmed as a primary driver in humans.

[park_bear in reply to pdpatient]

Why LLM AI / Claude is not appropriate to analyze science. "Claude is capable of a wide variety of conversational and text processing." text processing ≠ analyzing science:

Claude:

"This upends the previous belief that Parkinson's is primarily caused by protein aggregates like alpha-synuclein."

Study abstract:

science.org/doi/10.1126/sci...

"We identified a time-dependent pathological cascade beginning with mitochondrial oxidant stress leading to oxidized dopamine accumulation and ultimately resulting in reduced glucocerebrosidase enzymatic activity, lysosomal dysfunction, and α-synuclein accumulation."

[Emphasis added]

[pdpatient]

Claude further says

Here are some additional points about the article:

- LRPPRC stands for "leucine-rich pentatricopeptide repeat containing protein." It plays a key role in mitochondria by regulating gene expression and activity.

- Loss of LRPPRC led to mitochondrial dysfunction and motility issues in mice neurons, causing dopamine neuron loss and Parkinson's motor symptoms. This suggests mitochondrial health is central to disease development.

- The researchers were surprised to find LRPPRC pathology preceded alpha-synuclein aggregates in mice brains. This challenges the view that alpha-synuclein is the initial trigger that then causes mitochondrial defects.

- LRPPRC levels were also lower in human Parkinson's post-mortem brains compared to controls. While not conclusive, this hints it may be relevant to disease onset in people too.

- Exactly how LRPPRC loss leads to mitochondrial dysfunction needs more study. It could involve alterations in respiration, ROS production or electron transport chain activity.

- Genetic testing found no LRPPRC mutations in Parkinson's patients so far, implying other causes like environmental factors may be reducing its levels.

- Future research aims to confirm LRPPRC's role through genetic mouse models and explore if restoring its levels can slow or prevent Parkinson's onset.

- This work was a collaboration between biologists and neurologists, highlighting the importance of cross-disciplinary research to uncover new disease mechanisms.

In closing, this study provides an intriguing new perspective on Parkinson's origins centered on mitochondrial health and lipids rather than just proteins. More validation is still required but it opens promising angles for future therapeutic exploration.

[SilentEchoes in reply to pdpatient]

Complex 1 in the mitochondrial respiratory chain is associated with PD. I suspect the lipid disruption is caused by the insertion of a non protein amino acid that blocks the receptor, preventing the neuron from doing its job.

Thank you for this analysis, it filled in a lot of knowledge gaps.

SE

[pdpatient in reply to SilentEchoes]

Thank you but you need to thank Artifical Intelligence for the analysis👌😭😂. I am just the so called "prompter".

[SilentEchoes in reply to pdpatient]

Please introduce me to Claude!

[pdpatient in reply to SilentEchoes]

Here you go. Enrollment and use is free.

Here is the information about the chatbot/introduction :

anthropic.com/index/introdu...

Here is the updated link to join Claude for free.

claude.ai/login

Here is the link for using Claude through the third party chat portal called POE. POE is enabled to use the internet

Poe - Fast, Helpful AI Chat

poe.com/

Here is the prompt that I use

Analyze and summarize the information below

[SilentEchoes in reply to pdpatient]

Thank you! I think this is going to save me a lot of time.

[CuriousMe12 in reply to SilentEchoes]

AI is often correct but is known to sometimes tell lies now and then so I don't use it. And no one is accountable for the statement "it was AI"I'd advise cross checking anything it says.

[SilentEchoes in reply to CuriousMe12]

I'll still fact check - it help save time sifting through research and bring up related disorders I hadn't thought of. I'm always learning 😊

Thanks

[Ghmac in reply to pdpatient]

So PD, is an AI, and Claude is doing the process?

[pdpatient in reply to Ghmac]

Claude is an AI chatbot powered by the Anthropic language model . You will have to prompt it properly though. It's techno geek.

I hope you are not asking if I am real though 😂although I suspect that it might happen sooner than you think, maybe even on this platform They already tried it on other platforms business removed it due to concerns over integrity issues

[pdpatient in reply to Ghmac]

Ghmac, here is a simplistic explanation of what an AI chatbot is

Imagine having a friend who is an avid reader and has gone through a ton of books. Whenever you pose a question, they dig into the wealth of information they've acquired from these books to provide you with a pertinent answer. Now, replace this friend with a computer, and voila, you have a chatbot. A chatbot is akin to this knowledgeable friend, having "read" a large amount of text from books, websites, and other places. When you ask a question, it combs through this "read" material to deliver a suitable answer. The chatbot identifies patterns in the text it has processed, improving its ability to respond to inquiries over time.

Now, imagine giving your friend a magical magnifying glass, allowing them to instantly read new books or newspapers whenever they need additional information to address your question. This is akin to some chatbots having the ability to access the internet to fetch the most recent information when responding to your queries. Currently, POE ( another free chatbot) has that ability. The paid version of Claude and ChatGPT does have internet connection as well.

Moreover, continuing with the analogy, as you continue engaging with your friend, they become more accustomed to your manner of posing questions, and can refine their responses to resonate with you better. In a similar vein, advanced chatbots have the capability to learn from your interactions, thus providing more personalized responses as time goes on.

Behind the scenes, chatbots utilize complex algorithms and mathematical models to sift through vast amounts of text, pinpointing relevant information and constructing a coherent reply. However, on the surface, it's much like engaging in a conversation with a highly well-read friend who's adept at quickly looking up anything they aren't sure about right away.

[genesurf in reply to pdpatient]

"Imagine having a friend who is an avid reader and has gone through a ton of books"

Now imagine this friend has a fantastically creative imagination, and never ever wants to disappoint you by saying "I don't know". If you ask it a question, it might tell you the truth, or it might invent a plausible-sounding answer.

I love working with AIs, but unless the answer is in a well-traversed area of knowledge, I always double-check the answer by googling. You can also try telling it that you don't think an answer is right, and ask it to check its answer, although it will frequently double-down on a wrong answer. Best of all is to ask the same question in multiple ways in different sessions.

Or ask different AIs the same question, and see if they agree.

AIs are too eager to please, and they can't tell the difference between invented and factual material. In a sense, everything they say is invented, where they incorporate facts in their inventions where possible. But invention is at the heart of their answers, no matter what.

[SilentEchoes]

2/3 The synapse is the space between neurons, a dysfunctional (diseased) neuron sends it's toxic messenger (non protein amino acid) across the synapse to a healthy neuron. The healthy neuron has cell receptors with binding sites. It can only accept messengers carrying instructions if they fit the receptors. It's a lock and key relationship. If the key doesn't fit it won't open the lock. We need to know the name of the cell receptors. In ALS it's AMPA and NMDA, and I bet it's the same for this neuron group. If we know what the receptors are we can partially block them (you don't want block all cell receptors it has a bad outcome) and slow or stop the rate of neuronal spread.

SE

[SilentEchoes]

3/3 The cell receptors on dopaminergic neurons are AMPA and NMDA.

We, and I mean all of us are chronically magnesium deficient. You've heard it before but this is the why you need to supplement with multiple forms of Mg: magnesium is a NMDA antagonist, it partially blocks the NMDA receptors on neurons. Another NMDA antagonist is memantine.

The linked Wikipedia page also discusses Glutamate excitotoxicity. The cell receptors for AMPA and NMDA, and glutamate excitotoxicity are the same for PD and ALS.

Don't freak out, your chemical exposure is not the same as mine. When these toxic chemicals are inhaled all bets are off. The nose to brain pathway is well known and is being researched as a method of drug delivery. Inhalation of toxic chemicals bypasses all of the body's defense mechanisms for detoxification. If you have PD it's more likely than not that your form of toxic exposure was through food or toxins adsorbed to particles like dust and smoke that make it into the lungs. In any case it's small exposures over time that lead to PD. The problem is that you don't know it's happening until you've reached the tipping point.

Some of you aren't ready to hear me, the AMPA receptor antagonist is Ivermectin. There is a registered patent for this specific use. If you want to believe it's just an animal dewormer, that's your prerogative.

It's important to know that AMPA is the toxic metabolite of glyphosate.

You can more about ligand- gated ion channels here:

en.m.wikipedia.org/wiki/Lig...

sciencedirect.com/science/a...

en.m.wikipedia.org/wiki/NMD...

It's a lot. But know this - we've been lied to for decades about pathology and etiology of disease just to sell us pharmaceutical products that don't cure disease.

SE

[LeharLover62 in reply to SilentEchoes]

Hubby’s been on mementine for 3-4 years now and is sadly still progressing and declining. So that’s not enough, if this signaling issue is the cause.

[SilentEchoes in reply to LeharLover62]

There's more than one receptor. Nicotinic, which you selectively block with nicotine patches (people who smoke have lower incidence of PD) and AMPA which is selectively blocked with ivermectin. You also need to detoxify. If you block the toxins from attaching to the neurons they will get recycled or find somewhere else to go. Zeolite is a safe binder. thegoodinside.com/zeolite-d...

We need a multi pronged approach: 1) block the attack on the neurons, 2) detoxify the poison, 3) support the immune system and reduce inflammation. Sounds simple but it isn't.

[LeharLover62 in reply to SilentEchoes]

You may be right of course, but hubby was also a serious chain smoker until shortly after his diagnosis, so I’ve always been skeptical of the nicotine receptor theory (at least for him)

But I did just read an interesting study where zinc chelation cured a type of PD in mice, so that’s an interesting hypothesis.

I also wonder if the chain smoking introduced other toxins into his system.

[SilentEchoes in reply to LeharLover62]

The only acknowledged risk factor for ALS is smoking. Combustion forms formaldehyde. I'm a nonsmoker. Also, nonsmokers get lung cancer from secondhand smoke. I suppose smoking in general is bad for you - nicotine maybe not so much. There is a nicotine patch protocol for PD.

fight-parkinsons.org/wp-content/uploads/2016/05/Nicotine-Patch-Therapy.pdf

There's a lot more information if you search online.

[mk2002wi]

Very interesting. The scientists realized that Parkin has another important job that had previously been unknown.The gene also functions in a different pathway in the synaptic terminal — where it controls dopamine release.

Parkin is also a gingerbread. Ginger reduces inflammation and protects the brain from free radicals due to powerful antioxidants. It also improves memory function by increasing the neurotransmitters in our brain responsible for memory, focus, and reaction time.

Ginger even releases dopamine and serotonin.

[Jess123dog]

Dysfunction in the neuron’s synapses also occurs with Myasthenia Gravis I think, and the medication for that is Mestinon. For many with MG apparently Mestinon works really well. I know this because a Neurologist thought I had MG as well as Parkinsons (I have since been downgraded to Parkinson's only ). I have also read that some people are taking Mestinon (available over the counter in EU) for Long Covid.

[LeharLover62]

So I read through the research paper linked to in Science and was intrigued by the Petri dish PD neuron testing they did which would imply that if we can increase NAC or israpidine in the brain, we might stop the damage:

”

Mitochondrial antioxidants and calcium modulators attenuate the toxic cascade in DJ-1 mutant dopaminergic neurons

We found that long-term treatment with either the mitochondrial-targeted antioxidant mito-TEMPO or NAC blunted the accumulation of oxidized dopamine and improved lysosomal GCase activity and proteolysis (Fig. 3, A to D). Furthermore, because increased Ca2+ entry through Cav1 voltage-gated calcium channels enhances mitochondrial oxidant stress and dopamine synthesis (5, 18), we tested whether the Cav1 channel antagonist isradipine (19) or the calcium-dependent serine-threonine phosphatase calcineurin inhibitor FK506 (20) could also regulate dopamine oxidation. Both isradipine and FK506 significantly diminished the accumulation of oxidized dopamine (Fig. 3E), highlighting the importance of Ca2+ in regulating dopamine oxidation in DJ-1 mutant neurons.

“

science.org/doi/10.1126/sci...

(But that is old research from the same person from 2017)