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Researchers Neutralize Parkinson's Dopamine Killers
futurity.org writes with news that Iowa State researchers have made a breakthrough that could eventually lead to a cure for Parkinson's. Identifying the protein that kills the dopamine-producing cells in the brain has allowed the researchers to disable it and could be the first step in the development of new treatments. "Now, Kanthasamy’s group is looking for additional compounds that also can serve to neutralize protein kinase-C. By identifying more compounds that perform the function of neutralizing kinase-C, researchers are more likely to locate one that works well and has few side effects. This discovery is expected to provide new treatment options to stop the progression of the disease or even cure it. 'Once we find the compound, we need to make sure it’s safe. If everything goes well, it could take about 10 years, and then we might be able to see something that will truly make a difference in the lives of people with this disorder,' says Kanthasamy."
This research seems kinda shaky.
Since the disease leads to paralysis then death how safe does it have to be to be effective? If the cure kills 5% of the people that take it I would think that will be less than the 10 year delay in getting a "perfect" cure out of the lab and through FDA testing.
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It might do it for you if you had the disease.
If the side effects are more tolerable than the disease itself most people would opt to use the medicine. Waiting for perfect solutions has never really worked, especially for diseases that slowly rob you of any ability to manage your daily life.
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Yes, it certainly would be nice.
Especially when you consider there appear to be links between Parkinson’s, Alzheimer’s.
http://pn.psychiatryonline.org/cgi/content/full/36/20/23-a
There has been other research suggesting that understanding one of these diseases leads to avenues of research for the other.
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Personally, I'm more curious about why PKC is doing this: if we could figure out how/why the dopamine-producing cells are getting killed by PKC and reduce their vulnerability, that seems like it would be a less systemic way of getting the same result than trying to reduce PKC's activity. It'd likely have fewer side-effects since it would only affect the cells getting attacked, rather than all the other cells that need PKC for their normal function.
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I'm not so sure "neutralizing" this kinase-C will result in any miracle cures, as the protein happens to have a lot of other uses in the body, per wikipedia:
First of all, there isn't just one Protein Kinase C. There are a number of different versions with different jobs. Hence the list of the various isozymes in the article. The one in question is Protein Kinase C delta (PKC), and is NOT covered in the wikipedia article.
PKC mediates apoptosis, or programmed cell death, in certain dopamine producing neurons. By blocking the enzyme, you can prevent the apoptosis. Reading some of Dr. Kanthasamy's papers, it's clear that he's already found some agents that do this in animal models. This is, of course, a long way from human trials (10 years if things go well, I believe is what he said in the article). But this is very promising avenue of research.
What I can't figure out is why this is recent news. Dr. Kanthasamy has clearly been following this line of research for a few years. There's a 2007 paper entitled Neuroprotective Effect of Protein Kinase C{delta} Inhibitor Rottlerin in Cell Culture and Animal Models of Parkinson's Disease, so clearly he had already connected PKC with PD and was already investigating agents to block it.
There are many different forms of PKC, including PKC delta, the one that seems to be in question here according to recent publications from this lab. Specifically, a caspase enzyme is cleaving PKC delta into a smaller protein, and it's this cleaved version that appears to be causing the damage to the dopamine neurons in the nigra. Caspases mediate programmed cell death, and the compound in the paper I looked at blocks a certain caspase that was activated by the presence of certain metals.
So while PKC and caspases are found widely throughout the body, there's actually a fair degree of specificity in the current model. Of course it's still early, and there are things to worry about, such as a possible increased likelihood for cancer (caspase 3 may be involved in breast cancer). But if this particular interaction between capase 3 and PKC delta can be successfully blocked without harm to other systems, we may have a good treatment on our hands.
Sorry to reply to my own post but the PKC in question is protein kinase C delta, which is involved in a buttload of important pathways, and shutting it off would be problematic even if you could just kill it without messing with any other of the PKC family. PKC's are used throughout the body, since they add a phosphate group onto other enzymes, which is a sort of tagging system to mark the modified enzymes or activate them and allow them to do other things, but the specific effects/results vary depending on the cell. Metabolic and transcriptional control systems are *truly* complicated. So, in *my* (definitely not professional) opinion, I'm going to reiterate: it's very useful to have evidence that PKC-delta is responsible for killing dopamine-producing cells, but finding out why they're being killed seems a lot more useful theraputically than trying to reduce PKC-delta's activity/concentration. Maybe it's as simple as a defective cell-surface receptor that's getting modified by PKC-delta and we can target that, specifically.
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"Protein kinase C" is really at least 10 different proteins in humans- "isozymes" that have similar function, but different structures and different regulation mechanisms. All of the protein kinaseC variant belong to the larger class of serine/threonine kinases (about 100 different enzymes), and all the work that any of those enzymes do is to add a phosphate group to a serine or threonine amino acid on a protein. That role is important because protein phosphorylation is used as a molecular switch to activate or deactivate a protein. There's nothing special about this particular protein kinase-C isozyme, other than the target it phosphorylates.
Presumably, the target of this particular kinase C form is involved in the apoptosis pathway for dopamine-releasing neurons, so keeping the molecular switch from being turned on could prevent the cell death from being carried out. Since the structures of isozymes are different, you could develop a drug that knocks out this variant of PKC without turning off PKC globally.
However, preventing apoptosis of neurons, while possibly leading to an effective treatment, still does not address why brain cells would feel the need to kill themselves. For instance, in at least some Parkinson's patients, neurons suffer from a buildup of improperly folded protein called alpha-synuclein (compare amyloid and tau in Alzheimer's, prions in prion diseases). (However, overall there are many possible causes of Parkinson's and related syndromes, including unknown causes.) Cell suicide is meant as a protective measure for the remaining cells so they are not in turn poisoned by the output of misfolded proteins. What happens when you turn off apoptosis, and cells which turn "sick" are no longer able to die?
"FDA staff reviewers expressed concern about the number of patients who were left out of the study because they died."
It might do it for you if you had the disease.
If the side effects are more tolerable than the disease itself most people would opt to use the medicine. Waiting for perfect solutions has never really worked, especially for diseases that slowly rob you of any ability to manage your daily life.
Indeed. If and when it comes time to do trials in humans, they can probably expect to have volunteers lined up around the block. There are certain diseases where "we don't know if this is safe" is not that big a concern.
My godfather was in a study for an experimental treatment for a particular kind of leukemia. He was very close to entering the "acute" (as in acutely fucked) stage and the best matching marrow donor he'd found in years of searching would have left him with an under 10% chance of surviving the transplant if it came to that. He was sick and miserable thanks to his chemotherapy. So, what exactly did he have to lose? Not a whole hell of a lot. What was the outcome? The drug, as far as they could tell, cured him and everyone else in the study. All signs of leukemia vanished.
That's a long shot to happen in any particular case, but how many people who are facing nasty death if they don't try wouldn't be willing to take it?
On a related note, my graduate algorithms professor had a side gig of consulting for the medical industry. He related that he had worked on an algorithm for situations like this one, where as the study progresses and (assuming) the drug is showing signs of being effective you want to move people from the control group to the active group as quickly as possible while still maintaining the validity of the study. The algorithm was exponential in the size of the study, so study sizes or the ability to move people into the active group could be seriously constrained by available computing power. His optimizations (didn't change the big-O iirc) improved the performance and thus allowed larger study sizes and thus, as a result, could have literally saved lives.
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I don't know your intentions, but you seem to be insenuating a shift in the approach medicne is taking. I'd say there's not really a change.
Big breakthroughs in early medicne were things like antibiotics. Because the diseases they treat are caused by bacteria, and because you can eliminate all of the bacteria causing a given illness, cure is a reasonable goal.
Viral or fungal infections, or cancers, are similarly things where it makes sense to hope for a cure. Any condition that's caused by somethign attacking your otherwise-functional body might potentially be cured.
But as our lives get longer, and the number of deaths attributed to bacteria, etc. decrease, more and more of the conditions that have our attention are caused by some abnormal function of the body itself. The body is a complex and dynamic place; it's a bit much to hope that acute administration of a chemical will forever alter whatever defect is causing a problem. Suppose, for example, that the cause is ultimately genetic; then every cell is propagating the root cause. If you can interfere with the operation of the disease so as to eliminate - or sometimes even just reduce - symptoms, that's a great result; but it probably does mean you'll be on a maintenance medicine.
Modern medicine is still looking for cures, but the problems we're facing are a lot harder now that the lowest-hanging fruit has been taken.