"Parkinson's Disease: Working Towards a Cure" Part 3 -- Towards a Cure

This is the third post from a three part series written by Andrew Greene, a graduate student at McGill University studying Parkinson's Disease.

Rather than giving a broad, but ultimately superficial overview of modern research in the field of Parkinson's disease I'll try to delve more deeply into one particular line of research that I believe holds great promise. It's important to keep in mind, however, that there are many other exciting avenues presently under investigation around the world that could prove more effective. It's also important to remember that much of the research I'll be discussing is still very new, and the interpretations that myself and others are drawing from it have not yet been firmly established as correct.
     Let's begin by taking a step back and recalling that the movement-related difficulties that afflict those suffering from Parkinson's are largely due to the death of a subset of brain cells (neurons) known as the dopaminergic neurons of the substantia nigra pars compacta. The ultimate goal therefore becomes finding a way to stop these neurons from dying, but to do that we first need to understand why they die. This has proven to be an incredibly difficult question to tackle, and the laboratory in which I'm conducting my research is just one of many around the world that are dedicated to it. 
     Particularly puzzling is why these neurons, which I'll call SNc DA neurons for short, succumb when other groups of neurons remain healthy. The obvious answer is that they have intrinsic properties that make them different from other neurons, and this has led many labs to characterize SNc DA neurons in detail to try to find what makes them so special. James Surmeier's lab in Chicago has identified some particularly interesting attributes, which may very well contribute to the SNc DA neurons' selective vulnerability. Foremost among these is the heavy reliance of SNc DA neurons on an unusual type of calcium conductor called an L-type calcium channel. SNc DA neurons take in large amounts of calcium through these channels at regular intervals as part of their normal signaling processes. The problem is that despite calcium's important roles in bone formation and cell signaling it's actually quite toxic when too much of it accumulates within a cell like an SNc DA neuron (don't worry about drinking too much milk though, any excess calcium that you consume is stored in your bones, which makes them stronger and keeps the calcium out of sensitive areas; SNc DA neurons don’t take up so much calcium because the person they’re a part of is imbibing too much of the stuff, it’s simply a normal part of how they function). Because this calcium 'ingestion' is an ordinary part of an SNc DA neuron's second to second activity these neurons are equipped with miniature pumps that pump calcium out before it reaches toxic levels. However, these pumps require a massive amount of energy to power, and thus represent a heavy burden for the SNc DA neuron's metabolism. On top of this, SNc DA neurons each make approximately 370,000 output connections with other neurons, hundreds of times more than what most other neurons of the brain make. These output connections also require a massive amount of energy to maintain and operate, adding to the energetic burden imposed by the calcium pumps.
      How is all this energy produced? Cells have internal organs much the way people do, and the organs responsible for using the combination of oxygen and food to produce a cell's energy are called mitochondria. Each cell has many mitochondria that work collectively to meet the cell's energy needs. Because SNc DA neurons have such high energy requirements their mitochondria have to work double time. This is problematic because mitochondria produce toxic chemicals called reactive oxygen species as by-products of their effort to supply the cell with energy. The harder the mitochondria are working the more reactive oxygen species they produce, and these toxic chemicals can go on to damage various elements of the cell, including DNA and the mitochondria themselves. This damage accumulates in SNc DA neurons over a person's lifetime, and can ultimately lead to the neurons' death.
     If SNc DA neurons produce so many toxic molecules you may be wondering why they don't die off in all of us as we age. In fact they do, and what separates a healthy elderly person from someone with Parkinson's disease is how many have died. You can be pretty much symptom-free with up to 80% of your SNc DA neurons gone, but once you lose more than that you start to have serious problems.
    So why do some people lose almost all their SNc DA neurons and get diagnosed with Parkinson's disease while others reach ripe old ages without even getting close to the 80% threshold? The answer to that is almost certainly quite variable. In some cases it appears to be due to exposure to certain toxins that damage mitochondria and/or enhance the production of reactive oxygen species. In other cases the problem lies with inherited mutations that may increase reactive oxygen species production or affect a cell's ability to survive them. In most cases it's probably a little of each.
      Classic examples of the kinds of mutations that can lead to inherited Parkinson's disease are those found in two genes called Parkin and PINK1. The vast majority of genes, including Parkin and PINK1, are encoded in your genomic DNA, which is contained in almost every cell in your body. The DNA itself is essentially just a set of instructions, and generally doesn't take an active part in the functioning of a cell. The instructions encoded in each gene usually allow for the manufacturing of a particular protein, and these proteins are what perform most of a cell's functions. For example, it's now well established that mitochondria produce energy thanks in large part to a collection of proteins that lock together to form a molecular machine known as ATP synthase. ATP synthase acts much like a hydroelectric power plant, except that instead of using the energy from water flow it uses the energy from protons flowing through a small opening in a fatty membrane, which acts as a dam. The flow of protons quite literally spins a miniature turbine contained within ATP synthase, and the energy from the spinning of many of these turbines is used to power the cell.
      The proteins encoded by the Parkin and PINK1 genes are not directly involved in energy production, but what's becoming increasingly clear thanks to a landmark study by Richard Youle's lab in Washington is that they act together to perform a quality control function for mitochondria. As I mentioned earlier, one of the elements of a cell that can become damaged by reactive oxygen species is the mitochondria themselves. When mitochondria are damaged they often become less efficient and wind up producing more reactive oxygen species by-products, which can further damage themselves and the cell. The cell has mechanisms to repair mitochondria, but when mitochondria become so damaged that it's impossible to fix them they have to be eliminated to prevent them from running wild in their reactive oxygen species production. The Parkin and PINK1 proteins are responsible for identifying heavily damaged mitochondria and flagging them for a process called autophagy (literally meaning 'self-eating'), in which the cell destroys the defunct mitochondria and recycles their components.
     This is all well and good, except in people in whom Parkin or PINK1 are mutated. Mutations are errors in the DNA instructions, and they can result in the production of defective proteins. The mutated PINK1 and Parkin proteins that are found in Parkinson's patients are unable to perform the mitochondrial quality control survey undertaken by their healthy counterparts, which causes damaged mitochondria to accumulate. These damaged mitochondria function less efficiently and thus produce more reactive oxygen species by-products, putting more stress on cells. This is particularly detrimental for SNc DA neurons since, as discussed earlier, they are already heavily burdened in this department. Losing mitochondrial quality control processes probably explains at least part of why people with grave mutations in Parkin or PINK1 almost always get Parkinson's disease, usually at an abnormally young age.
    While the molecular and cell biology described so far is interesting in its own right, it also serves a critical role in designing treatments for Parkinson's disease. Since we are beginning to understand what might be killing SNc DA neurons we can identify ways to protect them. Anti-oxidants that soak up reactive oxygen species could be a good start, but there are others. For example, drugs that can enhance the mechanisms that eliminate defunct mitochondria may be able to reduce the production of reactive oxygen species in SNc DA neurons (and other cells) and thus slow the progression of the disease. Another promising therapeutic avenue is forcing SNc DA neurons to stop relying on the L-type calcium channels, thus reducing their energy requirements and corresponding production of reactive oxygen species. This has already been shown to work well in mouse models of Parkinson's disease, and will probably move into clinical trials in the near future.
    As I emphasized in the beginning, what I've described here is only a glimpse of some of the exciting discoveries that are being made in the field of Parkinson's research. There are now many competing theories to explain why SNc DA neurons die in Parkinson's disease, and time may prove one of them to be the most accurate. It seems more likely, however, that several of these theories are correct and there are a multitude of factors that contribute to SNc DA neuron death. The best treatment will thus probably not come in the form of a single drug, but rather a mix of molecules designed to protect SNc DA neurons from the various threats they face over the course of a person's lifetime.