Why do the dopamine producing cells die?

The number of dopamine-producing (‘dopaminergic’) cells seems to decrease with age, even in people without Parkinson’s disease.  And the incidence of Parkinson’s of course increases dramatically with age.  But something causes these cells to die more quickly in people who are eventually diagnosed with Parkinson’s disease, after the extent of cell loss crosses a threshold where clinically significant symptoms appear.

The first clue came from autopsies of people who had Parkinson’s disease.  In their brains, there were characteristic ‘inclusions’ inside brain neurons, roughly spherical, of varying size and somewhat irregular shape; these are now called Lewy Bodies.  These were determined to be composed primarily of proteins, especially the protein that came to be called alpha-synuclein.  We now know that (rare) mutations in alpha-synuclein can cause Parkinson’s disease, firmly establishing it as the most important protein associated with the disease.  Unfortunately, to this day, we have little understanding of its normal function, even though it is present inside nerve cells at rather high concentrations.  But we have learned a great deal about how things go wrong and cause the protein to form these insoluble aggregates that ultimately wind up in Lewy bodies.  More to come on that soon …

In the late 1970s and early 1980s, new clues emerged, in completely unexpected ways.  A series of illegal drug users developed symptoms of Parkinson’s disease after using a synthetic drug similar to heroin.  I won’t try to tell the story here, because there is a wonderful book documenting the discoveries, The Case of the Frozen Addicts.  The authors were Bill Langston, who made some of the critical discoveries and later founded the Parkinson’s Institute, and Jon Palfreman, an accomplished author and journalist, who was subsequently diagnosed with Parkinson’s disease himself.


This is MPTP

The key discovery was that the patients developed Parkinson’s disease symptoms (‘parkinsonism’) due to an impurity in the drugs called MPTP.  This compound had a huge impact on Parkinson’s disease research, because now it was possible to create animal models of the disease, in a short amount of time, with a chemical agent.  But it also muddied the waters in terms of understanding the cause of neurodegeneration in Parkinson’s.  The toxin destroyed the cells in a manner that seemingly has nothing to do with alpha-synuclein.  Instead, the toxin binds to a crucial component of mitochondria involved in creating ATP, the main unit of energy in the cell.  Mitochondria are fascinating organelles; the environment inside them is quite harsh, due to the formation of free radicals and other nasty compounds.  So the toxin doesn’t cause the neurons to die for lack of ATP, but rather due to damage inflicted from the messed-up mitochondria.

To this day, we still don’t fully understand how this all fits together.  But the genetics revolution has provided some pretty important clues.