At first glance, the movement disorder amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, and the cognitive disorder frontotemporal lobe degeneration (FTLD), which underlies frontotemporal dementia, manifest in very different ways. Furthermore, it is known that they mainly affect very different regions of the brain.
However, doctors and scientists have noticed several similarities over the years, and a new study in Cell reveals that the diseases have notable overlaps at the cellular and molecular levels, revealing potential targets that could generate therapies applicable to both disorders.
The new paper, led by scientists at MIT and the Mayo Clinic, tracked RNA expression patterns in 620,000 cells spanning 44 different cell types in the motor cortex and prefrontal cortex from postmortem brain samples from 73 donors. diagnosed with ALS, FTLD or who were not neurologically affected. .
“We focused on two brain regions that we expected to be affected differently between the two disorders,” said Manolis Kellis, co-senior author of the paper and professor at MIT’s Computer Science and Artificial Intelligence Laboratory. “It turns out that at the molecular and cellular level, the changes we found were almost identical in the two disorders and affected almost identical subsets of cell types between the two regions.”
In fact, one of the most notable findings of the study revealed that in both diseases the most vulnerable neurons were almost identical both in the genes they expressed and in how these genes changed their expression in each disease.
“These similarities were quite striking, suggesting that therapy for ALS may also apply to FTLD and vice versa,” said senior author Myriam Heiman, associate professor in the Picower Institute for Learning and Memory and the Department of Science. Cognitive and Brain Sciences from MIT. “Our study may help guide therapeutic programs that would likely be effective for both diseases.”
Heiman and Kellis collaborated with co-senior author Veronique Belzil, then an associate professor of neuroscience at the Mayo Clinic in Florida and now director of the ALS Research Center at Vanderbilt University.
Another key discovery of the study is that brain donors with hereditary versus sporadic forms of the disease showed similarly altered gene expression changes, even though they were previously thought to have different causes. This suggests that similar molecular processes could be failing in the origin of the diseases.
“The molecular similarity between the familial (monogenic) form and the sporadic (polygenic) forms of these disorders suggests the convergence of diverse etiologies into common pathways,” Kellis said. “This has important implications both for understanding patient heterogeneity and for understanding complex and rare disorders more broadly.”
‘Virtually indistinguishable’ profiles
This overlap was especially evident, according to the study, when looking at the most affected cells. In ALS, which is known to cause progressive paralysis and ultimately death, the brain cells most at risk are the upper motor neurons (UMNs) in layer 5 of the motor cortex. Meanwhile, in behavioral variant frontotemporal dementia (bvFTD), the most common type of FTLD characterized by changes in personality and behavior, the most vulnerable neurons are the spindle neurons, or von Economo cells, found in layer 5 of the most frontal regions of the brain.
The new study shows that while cells look different under the microscope and make different connections in brain circuits, their genetic expression in health and disease is strikingly similar.
“UMNs and spindle neurons look nothing alike and live in very different areas of the brain,” said Sebastián Pineda, lead author of the study and a graduate student jointly supervised by Heiman and Kellis. “It was surprising to see that they appear virtually indistinguishable at the molecular level and respond very similarly to diseases.”
The researchers found that many of the genes implicated in the two diseases involved primary cilia, small antenna-like structures on the surface of the cell that detect chemical changes in the cell’s surrounding environment. Cilia are necessary to guide the growth of axons, or long nerve fibers that neurons extend to connect with other neurons. Cells that rely most on this process, typically those with the longest projections, were found to be most vulnerable in each disease.
The analysis also found another type of neuron, which highly expresses the gene. SCN4B and which was not previously associated with any of the diseases, also shared many of these same characteristics and showed similar alterations.
“It may be that changes in this poorly characterized cell population underlie several clinically relevant pathological phenomena,” Heiman said.
The study also found that the most vulnerable cells expressed genes known to be genetically associated with each disease, providing a potential mechanistic basis for some of these genetic associations. This pattern is not always the case in neurodegenerative conditions, Heiman said. For example, Huntington’s disease is caused by a well-known mutation in the Huntingtin gene, but the most affected neurons do not express Huntington’s more than other cells, and the same is true for some genes associated with Alzheimer’s disease.
Beyond neurons, the study characterized differences in gene expression in many other types of brain cells. In particular, the researchers saw several signs of problems in the brain’s circulatory system. The blood-brain barrier (BBB), a filtering system that tightly regulates which molecules can enter or leave the brain through blood vessels, is thought to be compromised in both disorders.
Building on their previous characterization of the human brain vasculature and its changes in Huntington’s and Alzheimer’s diseases by Heiman, Kellis and their collaborators, including Picower Institute director Li-Huei Tsai, the researchers discovered that proteins necessary for maintain the integrity of blood vessels are reduced or lost in neurodegeneration. . They also found a reduction in HLA-E, a molecule thought to inhibit the breakdown of the BBB by the immune system.
Given the many molecular and mechanistic similarities between ALS and FTLD, Heiman and Kellis said they are curious about why some patients develop ALS and others with FTLD, and others with both, but in different orders.
While the present study examined the brain’s “upper” motor neurons, Heiman and Kellis now seek to also characterize the connected “lower” motor neurons in the spinal cord, also in collaboration with Belzil.
“Our single-cell analyzes have revealed many shared biological pathways between ALS, FTLD, Huntington’s, Alzheimer’s, vascular dementia, dementia with Lewy bodies, and several other rare neurodegenerative disorders,” says Kellis. “These common features may pave the way for a new modular approach to precision, personalized therapeutic development, which may bring much-needed new insights and hope.”
In addition to Pineda, Belzil, Kellis and Heiman, the other authors of the study are Hyeseung Lee, Maria Ulloa-Navas, Raleigh Linville, Francisco García, Kyriaktisa Galani, Erica Engelberg-Cook, Monica Castanedes, Brent Fitzwalter, Luc Pregent, Mahammad Gardashli, Michael DeTure, Diana Vera-García, Andre Hucke, Bjorn Oskarsson, Melissa Murray and Dennis Dickson.
Support for the study came from the National Institutes of Health, Mitsubishi Tanabe Pharma Holdings, the JPB Foundation, the Picower Institute for Learning and Memory, the Robert Packard Center for ALS Research at Johns Hopkins, the LiveLikeLou Foundation, the of the Gerstner Family, the Mayo Clinic Center for Individualized Medicine and Cure Alzheimer’s Fund.