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.)