Republished with permission from World Parkinson Congress
By Dr. Alberto Espay
Consider this thought experiment. While you were away, a fire broke out in your neighborhood. By the time a firefighting crew arrived, it was too late. Your house was burned. This is a photo taken of the scene. Can you help piece together the cause of the fire?
Photo by Chris Tuite/Associated Press.
Shall we all agree it was the bicycle’s fault?
Of course not! But this is the metaphor of our Parkinson’s origin story.
Let us now step into the early 1900s. We are zooming into a crime scene, invisible to the naked eye, by harnessing a new technology, the microscope. It is the dawn of the new frontier of neuropathology. Under the lens of a microscope, a brain slice from someone who died with a malady called the Shaking Palsy shows unusual clumps. Could they have caused the palsy?
Scavenging in the proverbial ashes of a past fire, the brain autopsy, these clumps came to be named after the first person to observe them as Lewy bodies and Lewy neurites, or, collectively, Lewy pathology. Without pausing to consider them victims, our forebears branded them villains. They must have triggered the fire. They were the arsonists.
Ever since then, we have believed in two main hypotheses*:
1. If your brain has Lewy pathology, you have Parkinson’s disease.
2. If your brain can be cleaned from Lewy pathology your disease will end.
*A hypothesis is a scientific idea which, by definition, is false until proven otherwise. Despite plenty of contrary evidence, these hypotheses have resisted falsification. Philosophy teaches us that unfalsifiable ideas are not scientific ideas. They are dogmas.
Before the end of last century, we learned that Lewy pathology is mostly made up of an important protein called alpha-synuclein. This protein is present all over the brain, made redundant with gamma- and beta-synuclein, and the gene coding for it has been preserved since prehistoric times. It does a lot for us –and much research is devoted to finding what else it is critical for.
But since Lewy pathology must be the cause of Parkinson’s, alpha-synuclein surely turns toxic –so let’s forget about what it does when normal and focus on its evil features when abnormal.
To do so, we need to examine a key episode of history also made on the ashes of a fire. In the early 2000s, neuropathologist Heiko Braak and colleagues examined the distribution of Lewy pathology in 41 brains of people who had Parkinson’s disease and 69 brains of people with Lewy pathology who never had neurological symptoms. They ordered these brains from least to most alpha-synuclein staining and made static data appear dynamic: Lewy pathology moves through the brain in six stages. Parkinson’s, they thought, occurs when the spread of such pathology reaches the midbrain, midstream their malicious march.
The two hypotheses above have shaped these action items in Parkinson’s research:
1. If we detect aggregated alpha-synuclein, we can diagnose Parkinson’s disease.
2. If we develop antibodies against alpha-synuclein, we can treat Parkinson’s disease.
3. If we figure out the shape of Lewy pathology, we can classify individuals affected.
Here is the problem: the complete lack of correlation between Lewy pathology and disease. Yes, pathology precedes disease as a rooster crow precedes dawn but you would think that the more the Lewy pathology, the worse the symptoms, and the more accelerated the death of neurons. None of this is true. Despite the implications from Braak and his team, the evidence has shown that alpha-synuclein aggregation is neither necessary nor sufficient for generating Parkinson symptoms or precipitating the death of neurons.
Yet, the “Braak hypothesis,” as it came to be known, has inspired research to prove, not falsify, that Lewy pathology replicates, propagates, spread from cell to cell.
The bar for the concept that Parkinson’s in particular, and neurodegeneration in general, was about a gain of anything —the gain of toxic proteins— should have been much higher than the more logical premise: that degeneration is about loss, of proteins and neurons. Whatever was found in the ashes of the fire could well have been the last soldiers, not the criminals.
The evidence has been hiding in plain sight. Loss of proteins is universal in Parkinson’s disease: when measured in spinal fluid (the liquid that surrounds the brain), the levels of key proteins, including alpha-synuclein, amyloid-β42, total tau, and phosphorylated tau are low compared to those of people without disease.
Low levels of proteins occur because they transform from soluble strings (meaning, they can be dissolved and quantified in liquid) to insoluble clumps, a configuration known as cross-beta or amyloid. This protein transformation “increases” Lewy pathology (makes it quantifiable) but also decreases normal protein levels. And that side of the Lewy pathology problem has, until recently, been invisible in research. Probing the Parkinson’s Progression Markers Initiative (PPMI) cohort data we have shown that the higher the spinal fluid levels of alpha-synuclein and amyloid-β42, the more brain there is. The lower the levels, the worse the brain atrophy.
Lewy pathology, therefore, represents the end of functional alpha-synuclein –not the beginning of a virus-like agent. From our knowledge of physics, proteins precipitate, not replicate.
Parkinson’s is not what it seemed. Forensic evidence creates narratives about a crime but rarely reveals the perpetrator. Lewy pathology is not Lewy pathogenesis –pathology is the end of many processes, the beginning of none.
Clearing Lewy pathology cannot restore the health of a degenerating brain any more than removing bicycles from the streets prevent neighborhood fires. Instead, increasing levels of depleting alpha-synuclein, as the acquisition of new bicycles, offer advantages worth testing. But moving efforts from clearing to restoring protein is nothing short of a paradigm shift. Are we ready to falsify the century-old hypothesis that synuclein is toxic and ‘ride’ the next century’s chapter on a more biologically and physically sensible paradigm?