October 2, 2019
Inside the brain, Parkinson’s disease is a selective assassin. The disease targets dopamine-producing neurons in a small region deep inside the brain known as the substantia nigra compacta (SNc), while largely sparing neighboring neurons and dopamine neurons elsewhere.
For decades, Parkinson’s researchers have tried to understand why the disease singles out these particular neurons in this particular region of the brain.
“Historically, researchers have looked for answers within the vulnerable SNc neurons themselves,” says Serge Przedborski, MD, PhD, chief of the Movement Disorders Division in the Department of Neurology at Columbia University Vagelos College of Physicians and Surgeons and a neurologist at NewYork-Presbyterian/Columbia University Irving Medical Center. He is also director of the Columbia Translational Neuroscience Initiative.
“But the cells don’t exist in isolation; they are surrounded by a host of other cells that may impact their susceptibility.”
New techniques have made it possible to examine these cells in unprecedented detail, and with a new center grant from the Parkinson’s Foundation, Przedborski and a group of Columbia scientists are now launching the first comprehensive look.
Microglia May Dictate Which Cells Die
Some evidence suggests that another type of brain cell, microglia, may act as an accomplice of sorts in the death of SNc dopamine neurons. Microglia are immune cells that clear away cellular debris and dead neurons in the brain, but they may have other functions as well.
“In Parkinson’s disease patients, we know microglia undergo morphological changes in the substantia nigra, and animal studies suggest these changes occur before neuron loss,” says Elizabeth Bradshaw, PhD, a neuroimmunologist at Columbia. “There may be some interaction between these cells that dictates which neurons survive and which ones die.”
Microglia have been difficult to study in the lab because they change rapidly when removed from the brain. But laboratory and computational techniques developed in the past few years have now made such studies possible.
Single-nuclei sequencing will give researchers in-depth details about what is happening in thousands of individual neurons, microglia, and other brain cells from Parkinson’s patients. (Tissue samples will be obtained from the New York Brain Bank, housed within Columbia University Irving Medical Center.)
The data collected from these cells will be analyzed with a machine learning technique developed by the project’s bioinformatics team. The analysis will compare cells in healthy brain regions with cells from regions affected by Parkinson’s to look for any signs that seem to be related to the death of SNc neurons, including interactions between different cells.
“Our approach may allow us to identify a different signature [of susceptibility] for each cell type,” Przedborski says.
A Comprehensive Look
Though some of the Columbia researchers suspect that microglia are hastening the death of their neuronal neighbors, the new project is designed to look at multiple cell types at once in an unbiased way. That way, the dataset can be reanalyzed by many researchers as new hypotheses arise.
“Researchers have looked at neighboring cells in the past, but those studies were biased by looking at only one cell type or brain region,” says Przedborski. “Our study doesn’t rule out any of the factors that may contribute to making dopaminergic cells more susceptible to injury than other brain cells.”
If the analysis reveals any clues, the researchers will test those in experimental models of Parkinson’s disease and determine if modifying key elements can alter the progression of the disease. Ultimately, the project could lead to new treatments for Parkinson’s or ways to detect it earlier.
Columbia University Irving Medical Center was one of four academic centers selected to receive a center grant from the Parkinson’s Foundation, which will provide $2 million over a four-year period to undertake a series of innovative, multidisciplinary studies with the potential to find major breakthroughs in understanding and treating Parkinson’s disease.
The idea that a signature or multiple signatures may reveal how microglial cells affect neurons is new, and there’s a chance it may not pan out. But even if the hypothesis is not proved, a lot can be learned from these studies.
“The Parkinson’s Foundation realizes that outside-the-box, multidisciplinary research holds the potential to find new treatments for patients, but there’s a risk that the interactions we find may not be that significant,” Przedborski says. “Even if that’s the case, information from our studies may still be helpful in identifying therapeutic strategies that protect the vulnerable neurons from dying, which could help a wide array of Parkinson’s patients regardless of what caused their disease.”