Using groundbreaking emerging sequencing technologies, Yale School of Medicine scientists are studying human brains impacted by Parkinson’s disease in unprecedented detail. This research is bringing them closer to understanding how the life-altering condition arises.
In a recent study, the researchers generated a cell atlas—a comprehensive reference that maps out all cell types within an organ—based on postmortem human brains from individuals with late-stage disease. Using single cell transcriptomics and proteomics, which enabled them to measure gene and protein expression, they compared how their findings differed from that found in healthy controls. Their findings revealed key differences, including that brains affected by Parkinson’s disease have greater levels of neuroinflammation.
The researchers also compared their Parkinson’s cell atlas to a previously published one that mapped cell types found in human brains affected by Alzheimer’s disease. They found that each disease has a distinct pathology that impacts the neurons differently but common signatures in glial cells and neuroinflammation. The researchers published their findings in Science Translational Medicine on October 30.
The research was led by Le Zhang, PhD, assistant professor of neurology and of neuroscience, Sreeganga Chandra, PhD, associate professor of neurology and neuroscience, and David Hafler, MD, the William S. and Lois Stiles Edgerly Professor of Neurology and professor of immunobiology at Yale.
“What we really want to do is learn how to prevent Parkinson’s disease,” says Hafler, who is also chair of Yale’s Department of Neurology. “This work in the brain is one more piece of the puzzle that suggests the importance of inflammation as a cause of the disease.”
Parkinson’s disease is a progressive neurodegenerative disorder that impacts millions of people around the world. The condition is characterized by loss of neurons in the substantia nigra, a region in the midbrain that produces dopamine. It is also associated with the formation of Lewy bodies—abnormal clumps of protein that develop inside nerve cells in the brain.
While Parkinson’s disease is primarily known for motor symptoms that result from the degeneration of dopamine-producing neurons, it also causes prefrontal cortex dysfunction. The prefrontal cortex is the region of the brain associated with complex cognitive functions such as decision-making, attention, and working memory. This region is also significantly impacted by Alzheimer’s disease.
Parkinson’s disease is linked to greater levels of neuroinflammation
Researchers have not had much insight into the underlying pathways that contribute to the onset and progression of Parkinson’s disease. Now, in their latest study, the Yale-led team ran multiple analyses on post-mortem tissue. By focusing their investigation on the prefrontal cortex, they were able to compare their analyses to previously reported data on Alzheimer’s disease.
The team ran two major analyses: single-cell transcriptomics and proteomics. Through single-cell transcriptomics, they isolated the nuclei of the brain cells in the prefrontal cortex and sequenced all of the RNA, known as “the transcriptome.” Then, they compared differences in gene expression found in brains with Parkinson’s disease against healthy controls.
Using the same tissue, they also ran a proteomics analysis, in which they used an analytical technique called mass spectrometry to measure protein expression in the tissues. This enabled the researchers to understand how the expression of proteins differs in Parkinson’s disease.
“Our study helped us understand the gene changes in Parkinson’s disease at the cell type level,” says Zhang. “By integrating this with our proteomics data, we can better understand the effects of the disease at both RNA and protein levels.”
The researchers found that brains with Parkinson’s disease showed signs of increased neuroinflammation, including elevated levels of two kinds of immune cells known as T cells and microglia.
Furthermore, they found that the presence of Lewy bodies was inversely correlated to the expression of a class of proteins called chaperones—these enable other proteins to fold properly and prevent them from aggregating—in excitatory neurons that regulate electrical signals in the brain. This finding could have therapeutic implications, the authors say. “If we could increase chaperone capacity in the brain, we could potentially decrease the abnormal aggregation associated with Parkinson’s,” says Chandra.
Next, the team looked for shared features between brains with Parkinson’s disease and Alzheimer’s disease. “We wanted to compare the two most common neurodegenerative diseases,” explains Zhang.
To their surprise, they did not find any overlap in gene expression within neurons. This suggests that the diseases likely impact neurons in distinct ways, the researchers say. “Parkinson’s and Alzheimer’s are clinically different diseases that have different mechanisms, and therefore the options to treat them will be different,” says Chandra.
Cell atlas will help guide future research
The study gave researchers important insight into how Parkinson’s disease arises. “Before the advent of these technologies, we couldn’t interrogate human tissue to get insights into disease progression,” says Chandra. “These analyses will help inform our future experiments and are a platform to raise pertinent questions that we can test.”
The team hopes their cell atlas will help guide the studies of research teams investigating Parkinson’s disease. In their own labs, the researchers’ next steps are to apply the same methods to brains in the early stages of the condition. In addition, they are looking at the blood and spinal fluid of patients, where they have also found signs of inflammation. Based on insights from these studies, the researchers plan to conduct clinical trials aimed at preventing the disease.