Prion or not prion?

In 2009 at the World Federation of Neurology meeting in Miami - where long-time NPF leader Nathan Slewett was honored - Stanford Nobel Laureate Stan Pruisner publicly stated what prion scientists had been saying for a while: there was good reason to think that Parkinson's disease was a prion disease.

Prion diseases were discovered by Prusiner who was trying to understand the nature of a disease that seemed to cause symptoms in patients (well, mice and sheep) without any transfer of DNA.  Proteins in the body fold into shapes, and often the mechanical properties from the shape of a protein is more important than the chemical properties.  Proteins fold through a process called "chaperoning," where one protein helps another to fold in a certain way.  Prusiner figured out that sometimes a protein can fold in a way that causes other proteins to fold in the same way -- a sort of self chaperoning.  Prusiner called proteins that with this property (and a couple of others) prions.  In this situation, if you think about it, each time a prion chaperones the creation of another one, it adds another chaperone, increasing the rate that misfolded proteins are created.  If a particular folded form of a protein is damaging, this results in disease.

A number of prion diseases have been discovered. It is required to be shown that the disease can be spread through exposure to the misfolded protein.  It has been claimed that this has been demonstrated in Parkinson's with a mouse study widely reported and replicated.  However some recent findings have cast doubt on this finding - was the protein actually chaperoning alpha synuclein accumulation?

One of the alpha biologists of Parkinson's is Northwestern's Jim Surmeier. He is the guy who is in all the hard-core biology sessions at conferences and usually asks the first, hardest question.  A Udall Center director, Surmeier challenged the audience at the most recent Udall Centers meeting.  If alpha synuclein were a prion, it would be transmitted from cell to cell either by proximity, across the extracellular matrix, or across synapses, the cell to cell junctions in the brain.  It turns out that the centers of alpha synuclein pathology are neither adjacent nor linked by axons. (Scientists trace the neural network using the rabies virus, which very aggressively spreads up -- from dendrite to axon, the opposite of neural signaling -- neuronal connections.)

Drug users who took the mitochondrial toxin MPTP (instead of the synthetic heroin they thought they were taking) were found to have selectively poisoned their dopamine producing neurons. People exposed to Parkinson's-connected pesticides selectively lose dopamine neurons, even though these toxins are general mitochondrial toxins.  There's something special about dopamine neurons.

The way Parkinson's pathology spreads, it seems like if prions are part of the Parkinson's story, it's not all of the story.

The primary model for thinking about Parkinson's progression in the brain is called the Braak hypothesis.  Hideko Braak is a Finnish neuropathologist (i.e., a guy who cuts up brains) and he has created well known mental models like this one for both Alzheimer's and Parkinson's.  The Parkinson's model shows the disease starting in the brain stem and progressing into the forebrain, meaning it starts with the regulatory parts of the brain and progresses to the cognitive regions.

This model is wrong. It offers a nice framework to think about Parkinson's progression, but this framework leaves out key details and misleadingly suggests that the course of Parkinson's is fixed and inevitable. It's not. For example, work led by Daniel Weintraub at the University of Pennsylvania (at another NIH Udall Center) has shown that patients who experience cognitive impairment will progress on to dementia. However, work by Antonio Strafella at the University of Toronto - supported by a grant I managed - showed that patients who don't have cognitive impairment seem to have cognitive regions of their brains bypassed by the Parkinson's pathology - the disease jumps across or somehow skips those regions.

So, although we know that Parkinson's is linked to misfolded proteins, we also know that those proteins alone don't define the spread of the disease.  One of the first places Parkinson's hits is a region called the basal ganglia, which is a region rich in dopamine producing cells, and we know that throughout the disease, dopamine replacement is a central part of treatment.

At the Udall meeting, Surmeier asked us to consider that maybe dopamine neurons are selectively vulnerable in Parkinson's. Other neurons -- not to mention other cells in the body -- have alpha synuclein but they don't get Parkinson's.  They have mitochondria but are not killed by mitochondrial toxins. At least not at first.

The prion model and the idea that Parkinson's essentially diffuses through the brain seems to be overly simplistic. It's probably part of the puzzle, but selective vulnerability is another part.

The scoop on nilotinib

In a prior post, I told the story of how a genetic mutation provided insight that can help everyone with Parkinson's.  The story of nilotinib is an exciting development leveraging that same model. As with isradipine, inosine, and other studies, this is a case where a fundamental understanding of biology informed the development of a drug we hope can make a difference.

Back in 1998, a group of Japanese researchers first connected the gene for a protein they named parkin with juvenile-onset Parkinson's disease.  Parkin is one of the most important genes for Parkinson's, representing the most important recessive genetic cause of Parkinson's.  Recessive genetic disorders (i.e., both parents must be carriers) are interesting to scientists because they are situations where people get a disease because a cellular process doesn't happen.  Since DNA codes for proteins, and humans have two copies of each string of DNA -- one from each parent -- only when both copies of the code for a protein are damaged does the DNA not work at all.  When that protein is important for a biological process to work, if the body can't synthesize it, that process won't happen.

Patients with parkin-related Parkinson's provide us with unique insight into the disease.  With alpha synuclein, there are lots of ways it could be problematic. With parkin, we know we can look just at the cellular processes where the protein is necessary.

Parkin is a protein that attaches to things in cells to trigger the process of garbage collection -- cells contain tiny structures, lysosomes and proteosomes, that are involved in breaking up things in the cell that are not needed. Both lysosomes and proteosomes have been linked to Parkinson's disease. A scientist I've supported, Ted Fon, is studying parkin. His team has shown that parkin is linked to mitochondria -- the power plants in cells.  Recent research has suggested that alpha synuclein converges with parkin at the mitochondria.

Since alpha synuclein is the most important protein in Parkinson's and parkin is second, this convergence probably points to something important.

As these connections are found, there is increasing enthusiasm for the idea that we could stop Parkinson's at the cellular level by addressing this "garbage collection" problem.  A team led by a brilliant scientist at Johns Hopkins named Ted Dawson figured out that a cellular chemical called c-Abl, which is a tyrosine kinase (this simply means that it is involved in regulating protein activity) and is connected to a form of leukemia, was also active in the brain.  Professor Dawson and his colleagues realized that c-Abl might be "turning off" parkin in the brain and that this was connected to Parkinson's.  If we could block c-Abl from turning off parkin, then maybe we could reverse the build up of protein in cells that we think is important in Parkinson's disease at the cellular level.

Funded through NIH's Udall Centers program, the Dawson Lab started looking at whether c-Abl could be inhibited. Other labs also pursued this target, including animal tests of imatinib and nilotinib, two leukemia drugs -- the latter by a biologist at Georgetown, Charbel Moussa.  The nilotinib results were promising and replicated at another lab.  Moussa found that nilotinib reversed alpha synuclein accumulation in a mouse model of Parkinson's.  The team at Dawson's lab also studied nilotinib, and recommended that a phase I trial be initiated.

Moussa, working with the director of the National Parkinson Foundation Center of Excellence at Georgetown University, a neurologist named Fernando Pagan, launched a clinical trial of nilotinib for Parkinson's.  The results of that trial were presented at the Society for Neuroscience meeting in Chicago this month.  The press focused on the symptomatic benefits, but most scientists will tell you that we can't tell the difference between the the drug effects and placebo effects in a trial like this.  (The story of intravenous glutathione -- positive open label, negative randomized controlled trial -- is an example.)  The best we can say about the phase I trial at Georgetown is that it could have contradicted the very promising animal studies, and it didn't: tests of patients' spinal fluid suggested that the benefit might be real.  [Update: Ted Dawson told the Udall Center Directors meeting that he felt the dose in the Georgetown trial was too low, so it's not clear what we might see beyond placebo benefit. Update 2: Moussa says that the lower dose is effective because we don't need to inhibit c-Abl all the time, just for for a portion of the day, since these cellular processes can occur very quickly. The dose effective in cancer inhibits c-Abl around the clock.]

Further testing is clearly required.  People often say this when they mean, "someone who is widely respected and/or gives out a lot of money has said something and I don't want to contradict them."  In this case, however, I mean what I'm saying: we need more testing.

There is good reason to believe that it is fundamentally possible to slow or stop Parkinson's, and it is possible that if we did that, the brain would recover... somewhat.  The discovery of c-Abl as a target was done through good science, with biology, hypothesis testing and replication and all the good stuff of serious science.  It is possible but certainly not definite that c-Abl inhibition is the path to do this.  However, remember that this is chemotherapy.  Chemotherapy has a bad reputation for side-effects with good reason.  There are other promising studies, too, and we need to trust the scientific process as much as we put our chips on one drug in the pipeline or another.

The Maze of Health Finance

(Originally posted here.)

From the outside, the flow of funds in healthcare appears simple: Society puts money into healthcare and we get out health outcomes and revenue for the healthcare industry.  This simplicity is misleading, however.  It’s easy to think that you’ve figured out how to revolutionize healthcare, based on observing that one simple relationship: we put a huge amount of money into healthcare and get fairly little health out.  In reality, healthcare is a lot more complex.  It is a maze of interlocking financial relationships, contractual obligations, and misaligned incentives.

Let’s imagine a guy named Joe.  Imagine Joe has a dog, Buddy, and Buddy gets sick.  Joe takes Buddy to the vet, let’s call her Michelle. Michelle tells Joe he is in luck. It looks like Buddy has a condition that has been the subject of recent study and a newly developed surgery can help Buddy.  Michelle’s partner, a surgeon, has been trained on the procedure.  Buddy needs a CT scan to figure out whether he needs the surgery.  If the CT scan is positive and Buddy needs the surgery, there’s a 10% chance that the surgery will kill Buddy.  Even if the surgery is successful, in the best case, dogs only live about 18 months after the surgery (that’s about 10 dog-years).  “Wow,” says Joe.  “That sounds expensive.”

“It is,” says the Michelle.  “The CT scan costs $1500.  If necessary, the surgery costs $6,000 and that’s assuming there are no complications.  You could be easily talking $10,000 or more.”

“Gee,” says Joe.  “That’s a lot of money, and I could spend it all and have Buddy die anyway.  Isn’t there a less expensive option?”

“Yes,” says Michelle.  “First off, even if the CT scan is positive, you don’t have to do the surgery.  There’s a chance that Buddy might just have a simple infection, and that’s what the CT scan is intended to rule out.  We could, I guess, skip the CT scan and just give Buddy the antibiotics in the hopes that he just has the infection, but if he doesn’t, he’ll die.”

“Hmmm…” Joe ponders. “That’s more than I saved up all last year.”

---

Now imagine that Joe is your insurance company.  Buddy is you.

It gets more complex.  Maybe Michelle’s veterinary practice has invested in an imaging center.  (The anti-kickback laws don’t apply to veterinarians.)  Michelle’s failure to refer patients for CT scans could affect the imaging center’s ability to make payments on the vendor-financed digital scanner.  Michelle’s partners were planning on the revenue from the imaging center to help pay their now-underwater mortgages.  Daytime use of the CT scanner is reserved for human scans, but insurance companies have negotiated such low reimbursement for scans that the fully-booked daytime use, after expenses, doesn’t cover the payments on the scanner.  The interest rate went up because, thanks to lower reimbursement, the credit rating of the center deteriorated.  The imaging center was relying on nighttime veterinary use in order to achieve positive cash flow.  Should Michelle have hard-sold the scan?  The surgeon in the practice was relying on Michelle’s referrals.  Without the scan, there’s no chance that Joe will even consider surgery.  Michelle, as a partner in the practice, would have gotten a piece of the imaging revenue and a piece of the surgery revenue.  Clearly, Michelle’s and Joe’s interests were not aligned.

Misaligned incentives don’t always result in bad care.  Today I work with a wonderful group of physicians.  Movement disorder neurologists are, in my experience, some of the most patient-focused physicians I’ve ever encountered.  There is a real debate about the value of services that generate tremendous profits for the hospitals that employ many of these doctors, and even some of those physicians who might be under the most pressure to deliver these services seem to be unafraid to express doubt in their value.

Having said this, I also know that there are physicians who do go the other way.  Drug, device, and test companies work hard to develop great products and sell them.  Banks finance capital purchases at hospitals and clinics.  Confirmation bias can be an insidious thing.  If a salesman has extolled the virtues of a drug, scan, or procedure, and, convinced, a physician invests in it, how likely is he or she to tell that patient who might benefit from it to wait and see?  Even more insidious, often the “salesman” is a respected colleague who developed it.  This is the least of the problem, as this scenario assumes an honorable physician: I’ve personally spoken to doctors who unabashedly explain that they make more money from their patients who maintain a moderate level of illness.

As an investment banker, I once got a call from a physician.  He was pitching to me the idea of my helping him raise money for a physician take-over of a failing hospital.  We said, send us the hospital’s financials.  The physician responded, “You don’t need to see the hospital’s financials.  They are terrible.  What you need to do is read Atul Gawande’s New Yorker article on McAllen, Texas.  Physician-owned hospitals make money.  It’s as simple as that.”  We were led to understand that the physicians would want the hospital to be profitable.  Whatever the debt service was going to be, the revenue would be greater.  If, for example, a neurosurgery practice was required for the hospital to get in the black, they’d get one.  Not only that, but they’d make sure it had patients.  I turned away the business; I don’t know if the deal ever got done.  There are rules that limit a physician’s ability to share in revenue from certain sources, but observation suggests that there are ways around this.

For the entrepreneur, these bad apples are actually the easiest to work with, as you can understand their motivations.  It’s the good and well-meaning parts of the system that make reforming medicine so challenging.  When I was a kid, my dentist looked in my mouth, probing my teeth and looking for trouble spots.  It took him 15 minutes.  My daughters’ dentist now has a technician x-ray their mouths. While my dentist used to have a staff of two hygienists, my daughters’ dentist has a staff of six.  My daughters’ dentist spends less than five minutes with her. Is the new way better?  Maybe it is: that’s the problem. I can’t help but noticing that this new way lets my daughters’ dentist charge a whole lot more for a whole lot less time spent per patient.  The sad thing is, between staff costs, negotiated rates and interest payments on capital investment, I wouldn’t be surprised to hear that both dentists, adjusted for inflation, got about the same income.  Yes, there are many new and revolutionary therapies that are changing people’s lives.  However, the major consequence of medicine’s increasing complexity seems to be, in many cases, increased complexity.

Looking for Answers

We all hope some day to be able to stop Parkinson's in its tracks. We want to stop Parkinson's forever, and even reverse the changes in the brain that result in Parkinson's, despite the serious challenges there are in making changes to the wiring of the brain. In my job, I have funded some of the work to make a pill that would stop Parkinson's, including work on the Parkin protein and alpha synuclein.

As I do this work, I am left with a question: what if we already know secrets that will change the course of Parkinson's, or they are right under our noses, and we haven't noticed?  Working with a smart new neuroscience Ph.D., I did some research to identify the impact of exercise on Parkinson's disease.  The results were dramatic.  Regular exercise -- just 2.5 hours a week -- seemed to turn back the clock on Parkinson's by about a year.  We don't have evidence that exercise changes what is going on in neurons in your brain, but we do think that exercise helps the cells in your brain to fight Parkinson's.

That's not it.  In another study, working with the Mayo Clinic's Anhar Hassan, we showed that there are many patients who out-perform the average, living with Parkinson's for 20 years or more.  While some in the PD20 cohort exhibited advanced disease, there did seem to be a group of what we might call "elite controllers" of Parkinson's disease.  These patients have been treated for years by leading experts at top academic medical centers, we think that they really have Parkinson's and are not misdiagnosed.

What if the secret to controlling Parkinson's disease isn't in a test tube in a lab somewhere but is, in fact, floating in the cells of one of these long-term thrivers?  I am hoping to launch a study to determine just this question: are there people whose cells are specially designed to fight Parkinson's, or are their cells deficient in some way that prevents progression?  If we could answer this question, we could then challenge our pharmaceutical company partners to figure out how to deliver this benefit to everyone with Parkinson's.

The first cure for AIDS was discovered in the bone marrow of a man who was immune to HIV.  We can cure "bubble boy disease" with tissue from unaffected people.  Small pox was eradicated using a virus found in nature.  We believe that many of the clues to Parkinson's in humans will be found by studying people with Parkinson's.  Many of the hardest questions for scientists are found to have been solved by nature, if we just knew where to look.

PS: many totally brilliant research findings are coming from biologists and researchers who are looking at molecular, cellular, or animal models of Parkinson's.  However, one of the most exciting findings of the past decade was a result of insight from studying patients who had a particularly bad form of Parkinson's, as I detailed earlier.  Studying people in the clinic and studying drugs in the lab form a virtuous circle.

Linking genes to cell function

In the 1990's, as scientists were conducting the human genome project, there was a belief that knowing the genome would explain all the mysteries of the body.  Once we could decode our genome, we could customize medicine for our unique makeup.

This turned out to be a little optimistic.

Genes contain the codes for proteins, and that's all they do.  Just knowing the code for a protein doesn't tell you much about that protein, though.  Sometimes we are lucky, and we find that a disease is linked to a protein whose function we already knew.  Most of the time it doesn't work like that.

Most of the time, a geneticist will study a group of people who have the same traits and look for common elements in their genes.  The story of alpha synuclein, the protein that many scientists now believe is closely tied to the pathogenesis (i.e., cause) of Parkinson's, offers a nice illustration of how this happens.

As I wrote earlier, alpha synuclein was discovered in 1994.  In 1995, researchers figured out what gene coded for alpha synclein and then, in 1996, a collaboration of NIH researchers with colleagues from the Robert Wood Johnson medical school and Seconda Universita degli Studi di Napoli showed that, in a large Italian family, they could link the family members who developed Parkinson's with a specific genetic location.  Soon after, again under the lead of Mihael Polymerapoulos at NIH, the team showed that this was the gene that coded for alpha synuclein.

Even when it was discovered, Polymerapoulos and his colleagues knew that the mutation they had discovered could not explain very much of the Parkinson's disease that neurologists were treating in their clinics - few people would have that specific mutation.  However, it didn't have to.  Knowing that the gene for alpha synuclein was important meant that it was likely that the protein alpha synuclein was important - but how?  In short order the next breakthrough came from the lab of Cambridge's Michel Goedert and his team: Lewy bodies, known to be present in the brains of people with Parkinson's since 1912, were composed of alpha synuclein.

Since then, further research has shed more light on the puzzle.  A group of leading neurologists figured out that Parkinson's seemed to be transmitted into transplanted cells.  This fueled the development of the prion hypothesis, that Parkinson's disease might be a prion disease.  Northwestern's Dimitri Krainc, when he was at Harvard, tracing the clues from another gene associated with Parkinson's, explained a part of this mechanism.  Others have provided more important clues.  

The importance of alpha synuclein to current research is well documented.  What's important about this story is that the genetic research didn't explain a genetic cause for the 15% of the disease that seems to be hereditary.  Instead, a mystery that started with one Italian family with a rare genetic defect started us on the path to understand all of Parkinson's disease.

The idea that knowing your genes will explain your health hasn't panned out.  Finding a genetic defect that causes Parkinson's isn't important just so that we can make genetic tests.  Understanding genetic defects that are linked to disease can identify mechanisms that are important in those diseases. We originally thought that genetic tests would tell us how to personalize medicine for you.  Instead we are finding that by understanding what genes are linked to aspects of each individuals health, we can identify ways to help everyone.

On the challenge of "cure"

We talk about "curing" Parkinson's, but what does "cure" mean?

If you talk about curing smallpox, I know what you mean.  You mean that a person might have the smallpox virus in his or her body, and you want me to make a drug that removes it.  I can visualize that: we need a chemical that will bind to the smallpox virus and activate the body's own systems for getting rid of stuff.  If you have cancer and talk about curing cancer, I know what that means: it means that you have some cells that carry mutated DNA that makes them cancerous, and you want me to get rid of those cells.

When we talk about a cure for Parkinson's, I don't think we all mean the same thing.

When you have Parkinson's, neurons in your brain get sick.  They stop working the way that they should.  The connections they make with other cells atrophy and disappear.  Eventually, the neurons die.  To be diagnosed with Parkinson's disease, you very likely have many neurons dead and gone.  (We all lose neurons as we age, just with Parkinson's some specific ones die faster.)  Other neurons get sick and atrophy, losing the connections that are central to brain function.

If a cure for Parkinson's means restoring the brain (motor? cognitive?) function to a level of functioning that is typical of people of the same age, sex, education, and activity level, that isn't a cure like a cure for smallpox or a cure for cancer.  It isn't just removing the other -- for example, a virus or defective cells.  It is removing an other -- misfolded forms of a protein -- and also replacing lost function.

Thus, mechanistically there is no way that one therapy would achieve both results -- stopping the pathology and replacing lost function.

We are pretty close to stopping the pathology.  There are trials right now (May 2015; EDITED 10/19/2015 -- the trial lined under the word "trial" has had very positive results published) hoping to stop or slow Parkinson's pathology.  Each of these is based on a good understanding of basic biology and/or population studies.  Each of these studies promises to at least shed new light on Parkinson's disease, even if they don't directly lead to a therapy.  It is worth noting that even a failed therapy provided the new insight to put us on track to today's most promising therapeutic targets.

In terms of replacing lost function, dopamine replacement therapy is the gold standard and represented a revolution in Parkinson's treatment that won its developers the Nobel Prize.  We can do pretty well at replacing dopamine.  We do much worse at restoring the function lost as other systems are attacked by Parkinson's.  Cell-based therapies, despite the hype and enthusiasm, don't work in controlled trials.  Outliers seem to benefit, but not better than outliers in studies of medical therapy.

The future of Parkinson's is most likely this: we will develop therapies that stop the progression, with some recovery of atrophied neurons (leading to some recovery-related dyskinesia and possibly hallucinations).  Lost neurons will not recover.  Once we can stop the pathology of Parkinson's disease, we will treat people at their earliest signs and we will be done with Parkinson's.

As far as restoring lost function, we do really well with medication today. As far as cellular solutions, if we could replace the lost cells in Parkinson's disease, we could replace the lost cells with natural aging.  It would be a fountain of (brain) youth.  We're probably not there yet.  Your brain ages for an evolutionary reason, and I don't think we're quite there in reversing this yet.

The change in our mental models of Parkinson's from being a disease of dopamine to being a disease of alpha synuclein have changed the meaning of cure.  I can imagine stopping the pathology of alpha synuclein, thus curing Parkinson's.  However, having cured the disease of alpha synuclein, people will still have symptoms of their alpha synuclein disease that linger on, for example, their lost dopamine cells.  A cure for the underlying pathology of Parkinson's won't eliminate the burden of the disease -- people will probably still need their sinemet -- but it will change our view of the future for people with the disease.

What is Parkinson's?

The Parkinson's disease community's rallying cry is "cure."  What is a cure for Parkinson's?  What do we mean by cure?  The first question we need to ask to answer this question is, What is Parkinson's?

To the best of our knowledge, most Parkinson's disease is what we call a synucleinopathy.  This means that it is a disease associated with a protein called alpha synuclein, or, sometimes in scientific shorthand, asyn.  Why alpha synuclein? The answer is a bit of a technical aside (you can safely skip the rest of this paragraph), you might find that people sometimes talk about proteins being "alpha helical" or "beta sheet" folded proteins.  This has nothing to do with the "alpha" in "alpha synuclein."  Alpha synuclein was one of two forms of synuclein identified in 1994.  One was called "alpha" and the other, "beta" -- thus, the word "alpha" doesn't really mean anything.  Alpha synuclein can form an insoluble structure called an amyloid, which sounds similar to the Alzheimers protein amyloid beta, but the word amyloid refers to a structure, not a protein, and the beta in amyloid beta and the alpha in alpha synuclein are also not related.  This is just one of those confusing things that scientists are taught and laypeople have to try to figure out, like why the galaxy in the constellation Perseus is called NGC 1277 while the galaxy in Andromeda is called M31.  It's just history, not science.

Back to Parkinson's.

In 1817, James Parkinson wrote the article that first described the disease, called An Essay on the Shaking Palsy.  This essay -- and our understanding of the disease from the earliest days until the 1970's, focused on the major clinical symptoms of Parkinson's that emerge from how the disease impacts the dopamine system, notably the dopamine-producing neurons of the part of the brain called the substantia nigra, which basically means, "black stuff," named in the days when anatomists just cut up corpses and named what they saw with little (and often wrong) insight.

In the late 1960's and 1970's, clinical researchers figured out that they could treat Parkinson's with dopamine replacement therapy.  Parkinson's disease was thus a disease of dopamine and therefore, we could focus on the dopamine system in treatments of Parkinson's.  End of story, right?

Wrong.

Focusing on dopamine for Parkinson's is like saying that harbor pollution is a disease of clams.  Replacing the shellfish in a harbor doesn't address the problem of pollution, and replacing dopamine (or the cells that produce dopamine) doesn't cure Parkinson's.  Parkinson's is a disease of cellular pollution (a topic for a later post), and to stop/fix/cure Parkinson's, we need to address that cellular pollution.

The better we address the dopamine system, the more clearly we can see how the synucleinopathy impacts other systems.  Bill Dauer of the University of Michigan recently received a Udall Center grant from NIH to study how Parkinson's affects the cholinergic system.  The cholinergic system is downstream -- affected after -- from the dopamine system, and we have no good treatments for its dysfunction.

Treating the dopamine system is critical to helping people with Parkinson's to deal with their symptoms.  However, focusing on the dopamine system, the substantia nigra, or other motor features of Parkinson's is a distraction from efforts to "cure" Parkinson's.

Why?

As a synucleinopathy, Parkinson's is disease of diffusion: misfolded alpha synuclein slowly but, so far, inexorably diffuses throughout the brain reaching far beyond the basal ganglia (the part of the brain associated with motor symptoms and containing the substantia nigra and other structures we talk about in Parkinson's).

The first breakthrough in Parkinson's treatment came from understanding how different parts of the brain were associated with how Parkinson's presented in the clinic and resulted in treatment by levodopa.  (Breakthrough 1.1 was when doctors realized that carbidopa made levodopa more tolerable: levodopa made people nauseous and carbidopa prevented that.)  The second breakthrough came from understanding how different parts of the brain interacted with each other and resulted in DBS.  Drugs like dopamine agonists and MAO-B inhibitors came from understanding how cells interacted.  The next breakthrough will come from understanding how molecules in cells function and this will herald a new opportunity to change the course of Parkinson's. (Linking genes to cell function will be another topic: now I've written that.)