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."

Comments

I don't know

[killmenow]

This research seems kinda shaky.

Re:I don't know

[Anonymous Coward]

But please, show some respect for those who are cursed with a disease or disability that they had no control over.

Like stupidity?

Re:I don't know

[Parlett316]

What about Ali? Maybe he should have bobbed and weaved instead of rope a dope.

Re:I don't know

[noundi]

I'm all for making fun of people who get injured by their own stupidity. I'm talking about the guys who decide to skateboard off of the roof of a 3 storey house, and end up breaking their penises or permanently damaging their scrotums.

But please, show some respect for those who are cursed with a disease or disability that they had no control over.

I find your code of ethics fascinating.

I find ethics fascinating.

Hmm, how safe is safe enough?

[afidel]

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.

Re:Hmm, how safe is safe enough?

[jrmcc]

If I am looking at a slow decline into the symptoms of Parkinsons and a nasty end, would I take a 95% shot at stopping the symptoms versus dying?

I'll take the meds!!

Re:Hmm, how safe is safe enough?

[ColdWetDog]

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.

Firstly, there are drugs that are moderately effective in Parkinson's Disease - not curative, but they do significantly improve patient functioning. Secondly, and most importantly, they found enzyme that they affects dopamine levels. They HAVE NOT (at least as far as I can tell from TFA) found that they can reverse the clinical entity known as Parkinson's disease by altering the function of that enzyme. That's first.

Then they have to find something (a drug or other treatment modality) that alters enzyme function that can get into brain (not easy) and not trash everything else in sight and / or create more problems than it solves.In this case, the bar is going to be set fairly high.

There are countless potential medical breakthroughs stuck at this stage. Very interesting, likely very important. Very speculative.

Re:Hmm, how safe is safe enough?

[afidel]

I'm more questioning the whole process of drug development and approval as it applies to diseases that are always fatal. I think the modern western approach has gone too far along the "it must be perfect for approval" path with the attached very high cost without showing that it has eliminated or even greatly reduced risk vs a more relaxed approval approach. Sure for a drug like Viagra perhaps the bar should be set high as the gain from the drug is fairly minimal in comparison to the potential problems but if you are talking about eliminating Parkinsons or non-Hodgkin's lymphoma then the bar should probably be lower as the potential gains are that it likely helps everyone it doesn't kill (who would have died shortly of the disease anyways).

Basically the reason so many cures are stuck at that early stage is that drug companies don't see a potential for profit because the system has become so cumbersome. I'm not normally a free-marketeer but perhaps the balance should be tipped back to the drug companies a bit for some classes of drugs?

Re:Hmm, how safe is safe enough?

[sjames]

You're at least comparing apples, oranges, and pears here.

The current meds can help alleviate the symptoms of the disease, but do nothing to arrest it's progress. Eventually, the disease progresses until the drugs cannot help anymore.

Various transplants aim to reverse the progression of the disease significantly. If it works, it's like starting over, but you still have a progressive degenerative disease and if you live long enough, you'll need another transplant.

TFA is talking about a drug that would halt the progress of the disease right where it is. Whatever your level of function is, that's where it will stay using only this theoretical new drug. Presumably, you would then use other methods to either reverse the progress (knowing it won't progress again) or to alleviate the symptoms.

Yes, it's quite speculative, but IF it pans out, it could be a major improvement in the lives of Parkinson's sufferers.

Re:Hmm, how safe is safe enough?

[Caged]

Be aware that this cure won't reverse degeneration that has already occured.

It will merely hault the progression of Parkinson's so that those in the future diganosed with this illness do not have to fear a slow, lingering decrease in their ability to function in society.

Sadly, this news is 20 years too late to help my father.

Re:Hmm, how safe is safe enough?

[Caged]

There are about 2-3 'stages' of Parkinson's medication, depending on just how much advanced the illness is at time of diagnosis. The first line of defence is the best and has good, manageable, results with relatively few side effects. The initial medication (typically L-Dopa tablets) regimen is effective for approximately the first 8-10 years, with the other stages of treatment decreasing rapidly in effectiveness plus worsening physical and mental side effects.

Remember that treating Parkinson's is essentially tampering with brain chemistry.

The current meds can help alleviate the symptoms of the disease, but do nothing to arrest it's progress. Eventually, the disease progresses until the drugs cannot help anymore.

Re:Hmm, how safe is safe enough?

[Qzukk]

if you are talking about eliminating Parkinsons or non-Hodgkin's lymphoma then the bar should probably be lower

The problem with this approach is that the worse the disease, the more snake-oil you can find out there, promising to cure you and your wallet of all of your ills.

Re:Hmm, how safe is safe enough?

[afidel]

You're making it a black and white issue, under your assumption it's either snake oil or it's a perfect cure. In the real world there are shades of grey and we are shooting for (and paying for) 99.9% black but are probably really getting 97% black when we get anything at all, many diseases go untreated because it's too expensive to develop a drug with a small potential patient set. What I'm proposing is relaxing things to a target of say 95% black when the disease warrants it. It's kind of like uptime in IT, most organizations don't need 5 9's uptime and can't afford it so they go for something more affordable which still brings significant benefits to the organization.

Re:Hmm, how safe is safe enough?

[IndustrialComplex]

The problem with this approach is that the worse the disease, the more snake-oil you can find out there, promising to cure you and your wallet of all of your ills.

For something that IS time sensitive like Parkinson's, I'd not lower the bar on claims, I'd lower the bar on the risk aspect.

In otherwords, lets say I make a claim that my drug does "A". I would like for the FDA to evaluate it for "A" and the major risks of "Will this likely hurt me more than help?"

Then once "A" has been sufficiently proven, and patients aren't immediately dying from liver failure or brain hemorrhages, I'd like to see the drug released with a medical disclaimer that it is still in the 'trial' phase and the negative effects have not yet been fully evaluated.

That way, you don't have snake oil (ineffective) treatments being sold, but you aren't holding off a treatment from someone who WILL die because the treatment may cause their hair to fall out. (Isn't that how we treat chemotherapy?)

Re:Hmm, how safe is safe enough?

[sonnejw0]

Protein Kinase C is a key enzyme activated by many very different pathways involved in many different functions across the board. Blocking it will affect innumerable systems.

Saying Protein Kinase C is the key to neutralizing Parkinson's Diseases is like saying Money is the key to the Financial Crisis. ... Duh.

The clinical effects of Parkinson's Disease are the result of neuron death. You can't reverse the effects. Even if you induce neuronal growth, the brain will have to relearn the connections it needs to make, which took a lifetime to form. Forget about playing the piano again. You'll have to relearn to play (although you'll still have the conceptual knowledge).

Skepticism may be warranted, here.

[dintlu]

They say the first thing you hear about research or technology is the best thing you will ever hear about it.

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:

"Recurring themes are that PKC is involved in receptor desensitization, in modulating membrane structure events, in regulating transcription, in mediating immune responses, in regulating cell growth, and in learning and memory"

Re:Skepticism may be warranted, here.

[smellsofbikes]

There are a bunch of different types of protein kinase c (known as isozymes: they do the same general thing, reduce the energy it takes for compound A to turn into compound B, but they're different enzymes) so one possibility is targeting only the PKC that's in the brain, and another would be to target only this specific isozyme, but I can't find anything that says *which* isozyme this one is.

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.

Re:Skepticism may be warranted, here.

[Pedrito]

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.

Re:Skepticism may be warranted, here.

[OG]

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.

Re:Skepticism may be warranted, here.

[smellsofbikes]

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.

Re:Skepticism may be warranted, here.

[reverseengineer]

"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?

Re:huh?

[icebike]

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.

So how does this relate to....

[lbalbalba]

... Certain typical Anti-Psychotic medicine, like Haldol, which typically exhibit the side-effect of Parkinson-like-symptoms ?

Re:Wouldn't it be nice if this were NOT vapor?

[icebike]

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.

Cure, eh?

[TheModelEskimo]

Have we seen any real cures via treatments lately? I honestly don't know, but there sure are a lot of maintenance-level medications out there. Is there a treatment or a pill out there that can just cure you flat out, when your body wouldn't do so on its own?

Re:Cure, eh?

[Anonymous Coward]

I would think that a drug that prevents a bad thing from happening is a cure. Yes, there are side effects, and yes, there are costs, but extending and enhancing quality of life is a pretty good definition of a cure to me.

There might, and probably will be, drugs that eliminate cancers. Once such things occur, it might/will be possible to reduce or eliminate dosage. Many other diseases are a lack-of or an excess-of in the body. Short of genetic modification, what you can do in these cases OTHER than to provide "maintenance-level medications". Hell, most people won't consider a GM tomato. How the @(&%!#@ will they do it to themselves??

Re:Cure, eh?

[mea37]

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.

Re:How do they calculate the time needed

[PotatoFarmer]

Probably has something to do with the length of time necessary to complete Clinical Trials for FDA (or equivalent regulatory agency) approval. Given that this process is still in the research phase and has not yet progressed to a testable drug state, 10 years sounds about right.

Re:How do they calculate the time needed

[jbeaupre]

This might explain why: http://www.usatoday.com/money/industries/health/drugs/2006-08-23-drug-lawsuits-usat_x.htm

Willing to risk the entire company by taking a few shortcuts? Ethically you might say it's worth it. Better for a company to risk death than a person. But that's not how things are decided. Both have to live. And that takes a lot of time.

Re:Parkinson's Disease questions

[reverseengineer]

Same substance, different parts of the brain. There are several different pathways that involve the release of dopamine; the mesolimbic pathway is where most of the behavioral functions of dopamine occur, and the nigrostriatal pathway, which is involved in motor control. In Parkinson's, the dopamine releasing neurons of the substantia nigra (at one end of the nigrostriatal pathway) die, leading to the characteristic motor symptoms. However, many drugs that act on dopamine pathways, particularly older ones, tend to be nonspecific, and can produce side effects from working on the other pathways- like the movement disorders associated with antipsychotic drugs, for instance.

Re:huh?

[Chris Burke]

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.