Since launching A Moving Disorder back in late February, I’ve been meaning to write a series of posts about the science of Parkinson’s disease. But I’ve found that it’s much harder to write about what makes Parkinson’s tick than it is to write about myself, or my family, or even shot-putting (a.k.a., the Sport of Kings). That’s because, even after two centuries of observations, experience, and research, much of the who-what-where of Parkinson’s remains a mystery. A casual researcher can quickly end up in the tall weeds, out where words and phrases like apoptosis, autophagy, synucleinopathy, and programmed cell death compete for space with qualifiers like poorly understood…unclear…elusive…not fully elucidated in dozens and dozens of academic papers.

I pride myself on being able to translate fairly complex medical and scientific topics into more easily digestible nuggets for the non-science reader. It’s a skill that has done me well in both my writing and my pediatric career. I tend to use a lot of analogies. (One example: a go-to way to explain an ear infection to weary parents was to compare it to faulty plumbing.¹) 

But, I have to say, Parkinson’s is straining my explainer-brain. I’ve started, stopped, and scrapped more drafts than I can count. For weeks, analogies came and went. For a while, PD was a war going on in my brain, or maybe an alien invasion; then it was, among other things, a sniper, a spy, an expert poisoner, and a hit man. Finally, it occurred to me: the best analogy to help explain the science of PD isn’t warfare, or contract killing, or even bad plumbing. It’s the old board game, “Clue.”

For the Clue-less, the game centers on a dastardly murder committed at the fictional Tudor Mansion in Hampshire, England. The object of the game is to identify: a) the murderer, b) the weapon used, and c) the room in the mansion where it all went down. Players assume the identities of the suspects (Reverend Green, Colonel Mustard, Miss Scarlett, Mrs. Peacock, Professor Plum, and Dr. Orchid*), then ponder the available weapons (revolver, dagger, lead pipe, candlestick, rope, and wrench) and location of the grisly deed (nine possibilities, anywhere from the Kitchen to the Conservatory. It’s a big mansion.) The first player with the correct who-what-where trifecta wins.

So, let’s apply a Clue-filter to Parkinson’s disease. What do we already know for certain?

Well, we know for sure there’s been a murder – more correctly murders plural – of millions of specialized nerve cells called dopaminergic neurons². We know, too, the room where the crime is taking place, more or less: the substantia nigra pars compacta³, an area deep inside the brain. We also know, that the cardinal symptoms of PD – bradykinesia, rigidity, and resting tremor – are due to the resulting low levels of dopamine in the brain. 

What don’t we know for certain? A whole lot of things, as it turns out.

We don’t know what the “weapon” is, for example. What evidence does Parkinson’s leave behind in its victims? If you could put any of those recently deceased neurons on a microscopic autopsy table and peek inside, you’d find the same thing over and over: unruly strands and clumps of a protein called alpha-synuclein, fatally gumming up the cellular works. 

But what does it all mean? Is alpha-synuclein directly responsible for cell death, or is it instead a byproduct of some other toxic process(es)? Although most research tends to point toward the former, how neurons die in Parkinson’s disease is still “not entirely clear,” or “poorly understood,” or “frustratingly elusive,” etc… (Clue-speak translation: alpha-synuclein is no lead pipe.) 

The Clue-concept of a “room” is shakier than I may have made it sound a bit ago, too. While it’s true that PD wreaks its havoc mainly in the substantia nigra, the damage isn’t limited to that location – other parts of the brain get whacked, too, and neurons in the gut, the olfactory (smell) system, and many other out-of-brain sites are also involved. It’s as though the murders took place (and are still taking place) in all nine rooms at once… plus the pool house, the scullery, the horse barn, and some bonus rooms you weren’t even considering. 

We don’t yet know the murderer’s identity, either. Decades of research have narrowed things down a bit: the culprit is probably a combination of a genetic predisposition and a toxin (or toxins) of some sort. But we don’t even know how many murderers there are. The list of genes implicated in the pathogenesis of PD is a long one; the list of potential toxins is even longer. 

There are 324 possible correct combinations of suspect/weapon/location in Clue. There are probably thousands of possibilities for Parkinson’s: the murderer’s identity remains murky, the weapon isn’t clear, but at least we’ve got a pretty good idea where the murders are taking place. 

One final, certain thing: when Parkinson’s disease finally gets sorted out, the solution to the mystery won’t be as simple as a) Colonel Mustard, b) in the library, with c) a candlestick. It may well be something like this: a) chemical manufacturers, b) in the cornfield, with c) herbicides or pesticides that are highly toxic to the human brain. 

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Footnotes:

1. It’s like this: in an ear infection, the eustachian tube – that tube you “pop” when you pop your ears, the one that connects the middle ear space to the back of the nose – acts just like a clogged drainpipe, but germs can still shimmy up the drainpipe from the nose to the middle ear space, and then…oh, never mind. It all made more sense if you were a sleep-deprived parent of a very fussy kid back in my practice heyday. At least I hope it did. 
2. I’ll be talking more about dopamine and dopaminergic neurons (the nerve cells that use dopamine to communicate with one another) very soon. 
3. Ditto for the substantia nigra – discussion to follow in a future post.