Interesting article. knowridge.com/2021/07/scien...
Scientists find the major cause of Parkin... - Cure Parkinson's
Scientists find the major cause of Parkinson’s disease
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Bolt_Upright
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Great! This may explain why Ambroxol benefits PD by increasing waste clearance from brain cells.
Hidden
in reply to JayPwP
it does, yes
All I really got from it was "blocked pathways" but that is interesting. Some treatments (HDT I think) aim to clear blocked pathways. It's just generalities, but still helps me conceptually (or steers me wrong).
I have had great results from HDT!
Hi, can u share more of ur HDT treatment pls. Source, dosage, type of HDT for eg.
The knowridge site failed to link to the underlying article. This appears to be it:
nature.com/articles/s41380-...
PIAS2-mediated blockade of IFN-β signaling: a basis for sporadic Parkinson disease dementia
That’s why we need to fast often to recycle and clean our cells.
So... I intermittent fast. I eat everything in an 8 hour window.
I wonder if I should add a day or 2 of all day fasting a week? It would not be hard for me.
Thoughts?
I eat also everything in an 8 hour window. Maybe this video help you to decide about that extra days.
Thanks delboy381! Maybe I need to tighten my window. The 8 hour window works well with my work schedule. I have about 6 hours where it is hard to step away. Great video.
Definitely
I think it's a good idea, altho 1/week may a bit too often (because we don't want it to become no fun.)
in reply to Bolt_Upright
I started with eating in an 8 hour window. I’ve adjusted to it and now that seems long. So, currently most days I eat in a 5 hour window. Sometimes as little as 3 hours. It took me a few months to emotionally adjust to this but physically it was an easy change. While me family is eating dinner, I sit at the table with my helmet. My children are going to have goofy memories of Mommy!
Thanks Park Bear for the redirect. I read it all.
Um so what did they say was the major cause of Parkinson's. I missed it some how
90% to 95% of all Parkinson’s Disease cases known as sporadic PD, is caused by a blockage of a pathway that regulates the nerve cell’s powerhouse, the mitochondria.
I'm curious about these "pathways". What are they?
From the park_bear link:
In conclusion, overexpression of PIAS2 in neurons causes pathology by triggering mitophagy block resulting in damaged mitochondrial accumulation and elevated oxidative stress, followed by increased oxidation of DJ1 and in turn inhibiting ERK1/2 and P53 by reducing their phosphorylation.
It is all very confusing.
We all need Dr. Shaun Murphy (The Good Doctor). 
I would question if scientists have found THE major cause of PD. I didnt notice them claiming that and articles that mislead just to get readership have me very skeptical. I think all we can say is this is research which adds to our knowledge of PD..
They all identify the PROBLEM, but not the SOLUTION!
Hi my friend! The solution is for them to edit the genomic defect. In the meantime, try fasting 16 to 20 hrs a day. This activates the vacuoles of the cells, which is basically a garbage disposal and recycling system. Clears the tangled proteins that are clogging up the system up there! Let me know how it goes after a few weeks .
The genomic defect is unique for every PwP. What you are suggesting is a temporary solution, and I believe every PwP has tried the fasting method. Have they gotten rid of PD? Fasting may ease symptoms but we are talking about a CURE!
Neurons don't die, they hibernate. Let the scientists find the substance that it would wake them up. That is my belief.
In the meanwhile, I highly recommend AMBROXOL, it's the closest thing to a CURE!
Despe, my good friend, I love you too much to argue, so I aint even gonna go there.
On line, platonic loves are the best, Bass!
Yes, he has for about a month and a half. I believe it's the only OTC disease modifying med! He started to be the person I used to know! Mental clarity is unbelievable, he is involved in anything I do, he laughs with jokes on TV and smiles at me like he used to! Improvements that I thought they were/are God's send. I started to question myself which of the two it really is.
That's wonderful! Yay!!!!!
have you been using AMBROXOL with your husband? How is he doing?
This is the good part (especially the end):
Discussion
Our aim in the current study was to recognize signaling pathways that are disrupted in sPD and its progression to dementia in sPDD. By transcriptomic analysis, we first examined the gene expression profiles of sPD patients by GSEA. By combining four independent transcriptomic datasets from sPD patients to create a discovery cohort, we found that the cytokine–cytokine receptor and its related JAK-STAT pathways were the most highly dysregulated pathways compared with healthy individuals. Moreover, to narrow the pathway, we identified strong association of sPD with dysregulated type I IFN signaling among the cytokine–cytokine receptor pathway. Furthermore, these data cement the relevance of defective type I IFN signaling to sPD, especially sPDD, given our findings that the lack of Ifnb or Ifnar1 in mice [9] leads to clinical features that resemble sPDD. Our additional analysis revealed that select genes in type 1 IFN signaling have a robust link to sPD and dementia. While some individual proteins involved in the type I IFN pathway had been studied in relation to PD, such as STING linked to mitochondrial dysfunction [56], it is the first time that dysfunctional type I IFN signaling pathway as whole is found associated with sPD.
Among the confirmed genes in the type I IFN signaling pathway, we identified PIAS2, the specific negative regulator of the IFNβ-IFNAR signaling [22], i.e., via specific inhibition of STAT2 [21] to impact the survival and function of neurons. Moreover, PIAS2 was significantly raised in neurons in the brains of sPD, and in particular in sPDD patients, paralleling our finding in Ifnb−/− mice. By knocking down PIAS2 in the brain of Ifnb−/− mice, the PD pathology and clinical manifestations were reversed. We next established that high expression of neuronal PIAS2 in vivo was sufficient to cause PDD-like pathology, and behavioral defects including cognitive impairments in healthy mice. PIAS2 overexpression triggered mitophagy block, resulting in damaged mitochondrial accumulation and elevated oxidative stress including increased oxidative DJ1, and in turn it inhibited ERK1/2 and P53 signaling by reducing their phosphorylation (Supplementary Fig. S4).
Our current findings are significant particularly because the molecular understanding of PD has been based primarily on the discovery of rare familial gene mutations, and although sporadic disease constitutes up to 95% of all PD cases [5, 6] and has been associated with such genes, its etiology remains unknown. Degenerative PD is generally regarded as a movement disorder, but up to 80% of patients will also develop dementia [57]. The importance of functional dopamine and dopamine-producing neurons in relation to movement disorder has received significant attention in the disease progression, but the underlying molecular mechanisms that drive the advancement from the loss of DA neurons to dementia are poorly understood.
Recent advances in genotyping by GWASs have enabled genetic risk factors that are associated with familial PD to be identified, but no evident gene or molecular factor has surfaced in the onset and progression of idiopathic disease. Furthermore, if overly stringent criteria are applied in GWASs, significant genes with an otherwise weak association with the pathology could be inadvertently disregarded, particularly in sporadic PD. Thus, if several such genes cooperate in a signaling pathway and collectively induce the PD phenotype, they would not be detected.
According to the IPDGC, when loci with weak association are included in the analysis of a GWAS, the estimated heritability of PD increases from approximately 4–27% [41]. This finding suggests that much of its genetic association lies below the thresholds for significance in the primary analysis, causing many true polygenic risk alleles to be overlooked [58]. Furthermore, PD is precipitated by a minor change in α-syn expression in patients with familial α-syn gene duplication [59] and perhaps by environmental factors that cause the complete dysfunction of otherwise subtle gene defects that coordinate in a given signaling pathway. These data indicate that sPD is not necessarily induced by genes with strong effects, underscoring the need to identify and consider weaker disease-associated genes as an entity. To this end, GSEA is a useful tool for discovering the relevant pathways and genes that predispose one and contribute to PD pathology.
In this study, we tested the hypothesis that sPD arises from the dysregulation of one or more genes, individually or cooperatively, in a specific signaling pathway which determines sPD and its progression to dementia in sPDD. Upon identifying dysregulated type I IFN signaling pathway in sPDD, to further characterize candidate disease-associated genes that had sequence variants in this pathway, we performed a meta-analysis of earlier GWASs on PD patients and detected many factors in IFNAR signaling that were enriched versus HCs. Thus, although these variants did not pass the stringent significance thresholds in the original GWASs, our results imply that this category of genes is pertinent to sPD.
Through transcriptomic analysis, we identified PIAS2 upregulation in all sPD patients with further increase in sPDD patients and established its pathogenic role. There are little data on the involvement of PIAS2 in PD pathology, and its contribution to PD and dementia has not been established. The JAK-STAT pathway, of which PIAS2 is a downstream effector [21], has been suggested to be associated with neurogenesis and to elicit neuroprotective signaling, but its blockade reduces microglia-mediated neuroinflammation in a model of PD [60, 61]. Furthermore, PIAS2 drives postsynaptic dendritic morphogenesis [62], albeit pertaining more to brain development and plasticity. These findings have created ambiguity with regard to the actual function of this pathway in PD, necessitating the identification of the molecular defects and pertinent cell types in this disease.
Consequently, we determined the contribution of PIAS2 to PDD. Neuronal expression of PIAS2 in the SN, STR, and prefrontal cortex of WT mice caused significant behavioral defects, including movement disorders, cognitive decline, and the loss of dopaminergic neurons—main hallmarks of PDD. Furthermore, we observed that PIAS2 has a negative impact on neuronal action potentials, which is compatible with its potential role in driving the cognitive decline in sPDD.
Based on these findings, our newly identified dysfunctional type 1 IFN signaling pathway, via PIAS2, is the first revelation of the involvement of an entire signaling cascade in the evolution of PD, including its development to dementia. Also, PIAS2 has been reported to interact functionally or physically with many components in this pathway, albeit in contexts other than PD. Based on our data, PIAS2 has potentially compartment-specific functions in neurons, regulating IFNβ-IFNAR signaling in the nucleus and cytoplasm with pERK1/2 and pP53 [63] as partners. For example, PIAS2 could negatively regulate type 1 IFN target genes by blocking STAT2 while governing the transcriptional expression of such genes as PARK7 [64], UCP2 [65], and TH, which are important for the regulation of neuronal oxidative phosphorylation and DA neuron survival. This differential regulation is consistent with the activity of PIAS2 in upregulating or downregulating target genes in MAPK signaling, depending on whether it is activated by ERK or p38 signaling [66]. A role for pERK/pP53 is also reported in autophagy regulation [52, 53]. In support, we observed that neuronal PIAS2OE upon blocking phosphorylation of ERK/P53 was associated with auto/mitophagy block and hence accumulation of damaged mitochondria. Previously, we have shown that neuronal lack of IFNβ-IFNAR signaling blocks auto/mitophagy and results in lack of cellular α-syn clearance, and hence its pathological accumulation [9, 32, 67, 68], In support, here we confirmed that PIAS2OE contributes to the accumulation of pathological α-syn and dysfunctional mitochondria with raise in oxidative stress markers, like oxDJ1, associated with inducing a mitophagy block, a process linked to neurodegenerative diseases including PD [69, 70].
PIAS2 is reported to regulate DJ1 activity [50], a transcriptional modulator, notably of P53 [71] and ERK [72], and antioxidant that has been linked extensively to PD. DJ1 has been reported independently to be a PD-associated protein, and the DJ1 L166P mutation is a rare genotype of the disease [73, 74]. The L166P mutation renders DJ1 improperly SUMOylated and prone to aggregation, causing it to colocalize with tau and α-syn in patients with Pick disease and multiple system atrophy, two neurodegenerative diseases [75, 76]. In our study, PIAS2OE in neurons upregulated DJ1 mRNA while increasing primarily its oxidation; accordingly, oxDJ1 levels are elevated in PD as a result of oxidative stress [77]. DJ1 governed by PIAS2 might act as an antioxidant by activating signaling factors, such as p53, to restore the redox balance [71]. Independently of DJ1, ERK signaling has been suggested to control p53 activity and thus regulate DNA damage-induced neuronal death [78]. Although our data presented here strongly support a major role for PIAS2 by blocking the classical IFNβ-IFNAR signaling pathway, i.e., counteracting JAK-STAT2, pERK/pP53, its downstream mitophagy and upregulating oxidative stress including oxidation of DJ1, a role for PIAS2 through SUMOylation regulation could not be excluded, particularly given the pleiotropism of the type I IFN pathway.
Thus, our findings imply that the dysregulation of PIAS2 potentiates the development of PD on several levels against an array of signaling proteins, the multifaceted functions of which converge to disrupt neuronal homeostasis and functions. Collectively, our novel findings render PIAS2 an exciting target for future therapeutic approaches in PD.
". . .future therapeutic approaches in PD."
I have read this conclusion hundreds of times. Give me a time window!!!
2 to 5 years this thing is done.
Very optimistic!
Did you ask Big Pharma, Bass?
just hang in there!
Trying to. . . You are such a good person, Bass.
This seems to be very important. But are there any practical implications for us at thid stage?
That may be a good research and promising if you can understand it. I’m too simple minded to get exactly what they are saying. But if it’s a move toward solving the mystery of how we get Parkinsons then…….keep on keeping on!!There is always HOPE!
How come we can’t down load the info it go’s to bad 400 spam , sorry
I was able to get to the PDF: nature.com/articles/s41380-...
Because I am not a scientist, just a layperson, I get down to the conclusion:
Collec-
tively, our novel findings render PIAS2 an exciting target for future
therapeutic approaches in PD.
Future, meaning what? Tomorrow is FUTURE!
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