AS accumulates in the appendix. - Cure Parkinson's

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AS accumulates in the appendix.

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pubmed.ncbi.nlm.nih.gov/338...

the human appendix contains an abundance of insoluble α-synuclein similar to what has been found in the PD brain 

appendectomy occurring decades before disease onset was protective against PD.

Collectively, our results suggest a model where pathological α-synuclein species, which are capable of seeding α-synuclein aggregates, are formed within the appendix. Our results signify that the appendix is a reservoir for pathogenic forms of α-synuclein, which may contribute to PD initiation and development.

Thus, a high degree of proteolytic turnover of α-synuclein is a likely feature of the appendix. Aberrant proteolytic turnover of α-synuclein has been hypothesized to play a role in PD pathogenesis, and several proteases that cleave α-synuclein have been identified (33–35). α-Synuclein truncation products are enriched in Lewy bodies (53–55) and can serve as potent seeds for further α-synuclein aggregation in experimental model systems (56). Thus, the appendix is rich in α-synuclein proteoforms relevant to PD.

???aberrant proteolytic turnover of AS has been hypothesized to play a role in PD???? This leads me to circle back to my prior post about the role of proteolytic enzymes. Could increasing proteolytic enzymes have a therapeutic benefit???

????please can someone explain this???

Thus, the proteolytic turnover of α-synuclein in the appendix might be important in generating protein conformers that are readily able to undergo axonal transport to the brainstem.

This signifies that α-synuclein aggregation in the appendix is a common phenomenon (much more common than PD) and therefore is not likely to be implicitly disease causing. Rather, it suggests that other biological processes that suppress the spread of α-synuclein aggregates or are responsible for the clearance of α-synuclein aggregates in the appendix may be crucial determinants in PD development. Hence, the abundance of α-synuclein aggregates in the healthy appendix signifies that, in certain individuals, there might be a “secondary hit” that aids in the accumulation and uninhibited spread of α-synuclein from the gut to the brain, eventually causing PD. In addition, removal of the appendix may reduce GI tract inflammation and thereby reduce systemic inflammatory cytokines, which contribute to PD as recent studies show (73–75).

****AS aggregates in the appendix but not only the appendix. Healthy controls also have AS in the appendix but must have a means of cleaving or ridding of it.***

????protease inhibitors???? Inhibitor is the opposite of what I understood**** other info I posted, posited that protease can potentially help break up, reduce AS.

Selective protease inhibitors, specifically for metalloproteases, have been developed and have undergone U.S. Food and Drug Administration testing for the treatment of cancer (78). Repurposing of these drugs to target the proteolytic cleavage of α-synuclein may be an effective strategy for the treatment or even prevention of PD. Furthermore, a key therapeutic solution may be to slow or prevent the spread of pathological forms of α-synuclein from the appendix through retrograde neuronal transportation to the CNS. Activation of the immune system, by noninfectious or infectious factors, can modulate PD pathology through the rate of accumulation and transportation of the α-synuclein aggregates (23, 79, 80). Thus, factors affecting the gut inflammatory and microbial environment, such as altering the gut microbiome 

One could further speculate that the appendix may be a site of initiation in PD cases with early GI tract abnormalities, whereas PD without prevalent prodromal GI tract issues may originate in other tissue regions, such as the olfactory bulb (82, 83). Future studies should examine whether the PD subgroup with prodromal GI tract dysfunction is protected against PD by an appendectomy.

*** starts in the appendix or the olfactory bulb***

ncbi.nlm.nih.gov/pmc/articl...

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Little_apple

Proteases are enzymes that cleave and hydrolyse the peptide bonds between two specific amino acid residues of target substrate proteins. Protease-controlled proteolysis plays a key role in the degradation and recycling of proteins, which is essential for various physiological processes.

sciencedirect.com/science/a...

Boscoejean profile image
Boscoejean

another version of this research: nih.gov/news-events/nih-res....

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Little_apple in reply toBoscoejean

“Parkinson’s. It appears that these aggregates—although toxic when in the brain—are quite normal when in the appendix. This clearly suggests that their presence alone in the gut cannot be the cause of the disease,” Labrie said.”

“Parkinson’s is relatively rare—less than 1% of the population—so there has to be some other mechanism or confluence of events that allows the appendix to affect Parkinson’s risk,” she explains. “That’s what we plan to look at next; which factor or factors tip the scale in favor of Parkinson's”

***if AS in the appendix is the norm amongst the general population than what is it about the PD gut that leads to misfolding and aggregation in the brain. My belief is that the following are disease pathology contributors.

1. Decreased or dysfunctional protein digestion. PWP have indican in their urine which indicates protein putrification.

ACTION: This can be decreased by protease / proteolytic enzymes.

2. Gut dysbiosis / leaky gut which is associated with also having a compromised blood brain barrier.

ACTION Resolve / reduce leaky gut with diet modifications ( bone broth, etc) No gluten, no lactose, low lectins diet, low sugar, etc

3. Speed up transit time, reduce constipation. Digestive enzymes as stated above and reduce / resolve hypochloridia

youtu.be/Nh-ezOkvd0Y

4. Improve glymphatic drainage ; not related to gut but related to accumulated toxins in the brain that are not being properly removed. This occurs mostly during sleep and given PWP sleep disturbances, this is a contributor. But, improving lymphatic drainage can only help to improve glymphatic drainage (this has been proposed and is being studied as it relates to long haul Covid)

??? It is emphasized that the vagus nerve is the or a means by which the AS gets from the gut to the brain. But, PWP have reduced vagul tone, function. I would then think that increasing vagul tone would be a disease driver unless doing so also increases the clearance of the brain.

Indican testing and C reactive protein testing would be good ideas IMHO.

Boscoejean profile image
Boscoejean

this is a presentation about the research

youtube.com/watch?v=fJz4eh6...

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