March 25, 2024

Brain atlas pinpoints vulnerabilities in ALS and dementia

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Using donated postmortem human brain tissue, a study reported March 22 in Cell undertakes cell-by-cell mapping and gene expression analysis to uncover genetic and transcriptional vulnerabilities and disease processes underlying two related neurological disorders, amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD).

The report introduces a comparative single-cell molecular atlas of the human brain’s motor and prefrontal cortices, based on single-cell RNA sequencing using tissue samples from pathologically normal donors and donors with ALS or FTLD — 73 donors in all. The atlas includes neuronal, glial, vascular and immune cells.

Involving some 625,973 cells, the atlas enables an analysis of remarkable depth and detail that would appear to be essential reading for anyone who studies these diseases or these brain regions.

FTLD is the process underlying frontotemporal dementia, the second most prevalent type of early onset dementia after Alzheimer’s disease.

ALS is the most common motor neuron disease. Estimated to affect as many as eight people per 100,000, it’s a fatal disease that progressively strips away the ability to eat, speak, move, and, ultimately, breathe.

The two diseases have strong symptomatic overlap and shared genetic contributors, and according to the paper, some 15% of patients with either disease receive a dual diagnosis.

Veronique Belzil, PhD, MS
Veronique Belzil, PhD, MS

“Certainly at the molecular level within given neuron types in a given brain region, our study indeed suggests that dysregulated transcriptional factors combine to render these diseases almost indistinguishable, irrespective of genotype,” said Veronique Belzil, PhD, MS, associate professor of Neurology at Vanderbilt University Medical Center and a corresponding author of the study.

“Mapping vulnerabilities at the molecular level to individual cells provides a valuable new perspective for understanding this disease spectrum,” Belzil said. “Details emerging in our atlas capture a number of previously unknown mechanisms and cell types at play behind these diseases, along with replicating known vulnerabilities.

“Painstaking studies with this depth and sweep are needed to advance the ongoing search for cures for these devastating illnesses.”

Belzil joined researchers hailing mainly from the Massachusetts Institute of Technology and the Broad Institute of MIT and Harvard in Boston. The report’s other two corresponding authors are Myriam Heiman, PhD, and Manolis Kellis, PhD, of MIT and the Broad Institute. The lead author is Sebastian Pineda, a PhD student at MIT.

The study expands the list of vulnerable cell types in these diseases. In both diseases the pattern of vulnerability goes beyond specific brain regions and cell types, showing a wide range of risk factors at the molecular level that can predict which cells are more likely to malfunction and die in various conditions.

Whether in sporadic or familial cases, across the two diseases known and previously unidentified neuronal alterations converge to near indistinguishability. Known genetic risk factors are more highly expressed across cell types implicated in both diseases.

The study implicates disease processes and effects not confined within a single cell type but instead involving interactions between different types of cells, including non-neuronal cells — so-called non-cell-autonomous pathological mechanisms.

The study was supported in part by the National Institutes of Health (grants NS127327, NS110453, AG067151).