Slashdot Mirror
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."
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.
Nostalgia's not what it used to be.
"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."
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.
... Duh.
Saying Protein Kinase C is the key to neutralizing Parkinson's Diseases is like saying Money is the key to the Financial Crisis.
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).