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.