In a healthy brain, the substantia nigra, or black substance, stands out as a black stripe against the pale gray and white matter of the brain. The substantia nigra is so easily observed, it was apparent from the first investigation of brains from patients with Parkinson’s disease (PD) that this brain region is severely affected in PD. You do not need a microscope to see that this black stripe in the midbrain is almost absent in end-stage PD. You do, however, need a microscope to see what is gained in PD—Lewy bodies containing the misfolded protein α-synuclein.

Lewy bodies are present in the substantia nigra of PD patients and are thought to be damaging to neurons. If you look through the brain, you can find many more regions with Lewy bodies as well, and neurons in these regions also show impaired function. If we examine brains from prior to PD onset through end-stage, a pattern begins to emerge. Lewy bodies are found first in the lower brainstem, then up through the brainstem and into cortical regions, which house cognitive processes. It turns out that the nigra is not the only region affected in PD; it may simply be a pit stop along a pathway to the cortex.

If PD pathology does indeed travel through the brain, how does it start? What pathways does it follow? Why are some neurons affected and some spared? We cannot probe these questions in humans, but we can mimic this process in mice. We introduce a small amount of misfolded α-synuclein into the brains of mice, and this misfolded protein acts as a template. Normal α-synuclein makes copies of the misfolded version, leading to aggregates that resemble the Lewy bodies in human brains. As in humans, aggregates in mice progress through the brain over time, allowing us to investigate this process.

Our group has developed methods to understand how brain pathologies progress though the brain over time. First, we needed to see exactly where pathology was, and when. We did this by making a map. Much like a cartographer mapping out a new continent, we moved through the brain, marking where pathology was and where it was not. Then we came back, later in the disease process to see how the landscape had changed. We repeated this process this over and over, until we mapped exactly where pathology was, and when. As we were busy charting the pathology landscape in the brain, other cartographers were mapping the roads through the brain, axonal connections that join one brain region to another and enable the brain to communicate.

Our pathology map, combined with the road map allowed us to ask a simple question: does PD pathology follow the roads through the brain? The answer was: yes and no. Yes, if we simply looked at all the regions that have pathology early. They were all connected to our seed site. But, no, because if we looked at all the regions connected to the seed site, not all of them developed pathology. We took this further, taking into account not just connections to the seed site, but all the connections in the brain. We predicted many of the regions that developed pathology, but some regions were resistant to developing pathology, while others accumulated more than we would have expected. It was time for another cartographer, one who mapped gene expression.

While every cell in our body contains the same genes, each cell uses certain genes more and certain genes less. This is what makes the heart the heart and the brain the brain. Within the brain, different cells have different gene expression related to their function. When we map gene expression, we can begin to understand how different cells function. Fortunately, another cartographer had decided to do this for all the genes in the mouse brain. We overlaid the map of gene expression for the α-synuclein protein on the road map. It turns out that many of those regions that accumulated more pathology than we expected had high α-synuclein expression, and the regions that had low α-synuclein expression were the regions that did not develop pathology, even though they had a road to the seed site. We think that misfolded α-synuclein travels existing roads through the brain, gassing up as it goes through self-replication; but some regions do not express α-synuclein, so misfolded α-synuclein cannot travel into those regions.

Several of the therapies now in clinical trials for treatment of PD are aimed at removing all the gas stations (α-synuclein protein) in the brain, so misfolded proteins have no ability to travel. Another therapeutic option is setting up roadblocks that allow normal proteins through but block misfolded proteins. The more we understand the disease process, the better prepared we are to properly target therapies. I have used the metaphor of a car trip to explain pathology spread because that is how well we understand the process now. Perhaps one day, a more appropriate metaphor will be a train schedule, and we will know exactly when and where to meet these pathological processes to derail disease progression.

Michael Henderson, PhD is an Assistant Professor at the Van Andel Institute. Dr. Henderson will be presenting at talk on this subject at the WPC Virtual Congress  in May. His talk will look at Tau co-pathology.

Ideas and opinions expressed in this post reflect that of the author(s) solely. They do not necessarily reflect the opinions of the World Parkinson Coalition®