Real Progress in Parkinson’s

https://blogs.sciencemag.org/pipeline/archives/2018/11/02/real-progress-in-parkinsons

by etiam • 8 years ago

140 20 8 years ago

blogs.sciencemag.org

mabbo• 8 years ago

Knowing nothing of biology, I wonder what we can do about misfolded proteins?

Can drugs be developed that can chemically attack the misfolded proteins without harming other ones?

etiam2• 8 years ago

There are natural substances which promote transition to the benign form (see e.g. https://en.wikipedia.org/wiki/Chaperone_%28protein%29) so it must certainly be possible to work with. But I don't know to what extent humanity has developed drugs to affect it so far.

gumby• 8 years ago

Sure: your immune system is a mechanism for finding proteins and binding to them, so you could in principle inoculate people against the conformations you don't want.

I'm not sure that would be a good idea as you know which ones you don't want in certain situations but you likely have no idea if the same ones are useful elsewhere.

BTW if by "drug" you mean small molecule monotherapy, I rather doubt it.

amelius2• 8 years ago

Some searching gives this suggestion: increasing the abundance of heat shock proteins by taking a sauna several times a week. Not sure if and how much this would really help.

DenisM• 8 years ago

Inhabitants of Finland are know for doing this. Do they have smaller incidence of Parkinson's?

DoreenMichele• 8 years ago

I wonder what we can do about misfolded proteins?

I kind of skimmed the article and went to the Wikipedia link they included for the protein in question. I don't really understand Parkinson's pathology and I've never heard of this aspect of it previously.

But I have a genetic disorder that involves a defective protein and I can speak generally to pathology of that sort, though I can't say for certain how well this applies in this specific case. What I skimmed sounds vaguely similar to the pathology I have read up on for my own condition.

In my condition, what happens is you have two of, say, 1600 or so different alleles (or two copies of the same one) that impact the coding of the CFTR. The CFTR is a protein that forms a cell channel that manages traffic of specific molecules into and out of the cell. The manner in which it is defective varies, depending upon the alleles.

CF is a progressive condition. In other words, it gets steadily worse over time.

I have never gotten any kind of logical explanation from the medical literature for this well established fact. I did my own digging. (I actually was trying to understand something else when I tripped across the following info, but I'm sure no one cares.)

It turns out that derangement of cell chemistry in terms of pH balance and/or salt causes protein misfolds. CF promotes both of those chemical derangements. My inference is that as the body gets more chemically deranged, you see more misfolds. As you see more misfolds, you have fewer functional CFTR channels. This creates a positive feedback loop, aka vicious cycle. Thus, "The normal progression of CF" -- ie you get steadily worse over time.

The misfold matters because basically the way it is folded is what turns a protein string into a useful tool for the cell. Think of Legos or something like that. I mean, that's not a good example. There are toys out there that can be strung together and then bent or whatever. I just can't think of the right name of a good brand.

But you have protein bits that get strung together and if they bend the way they are supposed to, you have a useful tool to accomplish important work in the cell. If they don't, you have a pile of junk that the body needs to expend additional resources on to melt down and either recycle or dispose of as trash.

So the odds are good that Parkinson's involves some specific vulnerability different from my condition and it is made worse by chemical derangement within the cells. Drugs (or dietary changes) that corrected the chemical derangement or prevented the chemical derangement would likely be a good thing to look at.

Correct the cell chemistry, you should see fewer misfolds. Fewer misfolds enhances performance, if only by not wasting resources on churning out a pile of junk proteins that can't be used and now need to be disposed of somehow.

mrfusion• 8 years ago

Has anyone researched if there’s an appendix link to Alzheimer’s ?

novalis78• 8 years ago

Fascinating, especially on the heels of the Herpes-Alzheimer connection discussed the other day. https://news.ycombinator.com/item?id=18265115

corpMaverick• 8 years ago

Interesting thread. There is a real need for medical specialists to faster share information and have high quality discussions. Increase the speed of feedback loops on ideas and research. Similar to what we do in HN. The software is the easy part, but it needs to be lead by individuals with high convening power in the field.

darkerside• 8 years ago

But where in the gut does misfolded alpha-synuclein originate, and why does it form? The working theory is that it’s formed after repeated immune response in the GI tissue.

Immune response in reaction to what? I'm not sure how closely leaky gut syndrome is associated with pseudoscience by the HN crowd, but seeming connections like this make me wonder if there's credence to it.

etiam2• 8 years ago

Immune response in reaction to what?

Foods we're not biologically adapted to eat, for instance?

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3705319/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3402009/

kelseyfrancis• 8 years ago

Immune response in reaction to what?

Autoimmune diseases like Crohn's and colitis?

amelius2• 8 years ago

I thought this was a good comment on that page:

Before we get too excited: it could be an epiphenomenon. For example, misfolded Alpha Synuclein leads to poor gut motility and that causes appendicitis, which leads to appendectomy. All retrospective studies are contaminated by that possibility, which is why treatments can’t be based on them. However, retrospective studies lead to hypotheses that can be tested in trials. Perhaps not doing appendectomies in people without appendicitis because they are “at risk” for PD–thats a bit extreme.

mhkool• 8 years ago

I wish they do not develop an inhibitor drug but try to find the cause of the inflammation. The big question is "what triggers the NLRP3 inflammasome?" Is that a combination of toxins? Or maybe Aluminum? https://www.ncbi.nlm.nih.gov/pubmed/18624356 states "These results indicate that alum induces IL-1beta via the Nlrp3 inflammasome but this activity is dispensable for alum-mediated adjuvant activity." So the root cause could even be vaccines with Aluminum.

caycep• 8 years ago

Dislike the title. Not like there hasn't been other "real progress" in Parkinson's elsewhere. Yes, there is a burgeoning gut-brain line of thought in PD but it's not the only thing. Furthermore, the study that is referred is a retrospective case-control study - yes this picks out signals in historical records, but this would be considered a preliminary statistical sign that a prospective, randomized trial would have to try and replicate.

https://www.ncbi.nlm.nih.gov/pubmed/?term=0+RESEARCH+ARTICLE...

Additionally, I would characterize this as one of many things to be excited about in the PD research / clinical world today:

For example - things that would be useful to patients - characterization of GBA mutations and new therapeutic compounds in the pipeline. Same with LRRK2.

For more in the gut-brain line of thinking - the use of GLP agonists medicines - first shown to be protective of islet cells in the pancreas in diabetes, in a human randomized control trial that showed decreased decline in Parkinson's disease vs. placebo controls.

All of these are something other than a "Me too" dopamine drug.

Plus RT-QuiC techniques for an actual blood test for Parkinson's....

I don't have to mention deep brain stimulation (DBS), which has been around for 3-4 decades, but the newer devices and techniques have an effect size in blinded trials that equal or exceed the effect size of previous trials that were open label...

person_of_color2• 8 years ago

Any SV startups working on PD or similar? My dad has it and I would like to work on it. Embedded systems engineer working on SoCs here.

thaw13579• 8 years ago

Not a startup, but Medtronics makes deep brain stimulators for PD that involved embedded systems work

person_of_color2• 8 years ago

They're old school. Would take years to do real engineering there and not filling out paperwork.

Real Progress in Parkinson’s

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