Multi-regional Transcriptomic Profiling Reveals Divergent Molecular Mechanisms in ALS-related Neurodegeneration
Yu-Wen Hsu, Yu-Ning Lu, Mingming Liu, Jiou Wang
Abstract
Neurodegenerative disorders including amyotrophic lateral sclerosis (ALS) remain largely unsolved, with complex etiology yet to be fully elucidated. The most common genetic cause of ALS in both familial and sporadic cases is the expansion of a hexanucleotide repeat in the C9orf72 gene. To systematically dissect the molecular landscape of ALS, we performed integrative transcriptomic analyses across multiple central nervous system regions from ALS patients carrying pathological C9orf72 repeat expansions (ALS-C9) and those without the mutation (ALS-non-C9).
Introduction
Neurodegenerative diseases are unified by the gradual failure and death of neurons, leading to irreversible impairment of the nervous system functions. Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder, marked by the degeneration of upper and lower motor neurons in the brain and spinal cord, which drives decline in motor control, muscle weakness, paralysis, and ultimately respiratory failure. Many ALS cases exhibit an aggressive course, relatively selective neuronal vulnerability, and overlap with frontotemporal dementia (FTD), thus providing a powerful model for uncovering the molecular principles that govern neuronal survival and death.
Materials and Methods:
Survival analysis was performed to assess the correlation between clinical and genetic factors, and disease progression in ALS patients. Survival duration was defined as the time interval between symptom onset age and age at death. Kaplan-Meier Curves were applied to visualize survival distribution. Cox proportional hazards regression models were applied to estimate hazard ratios (HRs) and the influence of covariates.
Discussion:
Our present study uncovers how genetic background and sex intersect to shape the molecular architecture and clinical duration-associated transcriptional dynamics of ALS. By leveraging multi-regional transcriptomic and cellular data, we identified both shared biological processes across ALS patients and distinct molecular features that differentiate ALS-C9 from ALS-non-C9 subtypes. Our analysis revealed disease-relevant pathways, stable versus transient molecular signatures, and cell-type composition changes associated with disease state and clinical duration.
Acknowledgments:
We would like to thank Dr. Henry Wong Sung Ching for discussions and technical supports.
Citation: Hsu Y-W, Lu Y-N, Liu M, Wang J (2026) Multi-regional transcriptomic profiling reveals divergent molecular mechanisms in ALS-related neurodegeneration. PLoS Genet 22(7): e1012225. https://doi.org/10.1371/journal.pgen.1012225
Editor: J. Nicholas Cochran, Hudson Alpha Institute for Biotechnology, UNITED STATES OF AMERICA
Received: September 15, 2025; Accepted: June 25, 2026; Published: July 8, 2026.
Copyright: © 2026 Hsu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: The original data were downloaded from the New York Genome Center (NYGC). The data that support the findings of this study are publicly available from the Gene Expression Omnibus (GEO) with the identifiers GSE137810, GSE124439, GSE116622, and GSE153960, and can also be accessed via DOI 10.1038/s41586-022-04424-7.
Funding: This work was supported by the National Institutes of Health (NIH) (NS074324 to JW; NS089616 to JW; NS110098 to JW; NS128494 to JW), the Walder Foundation (to JW), the Packard Center for ALS Research at Johns Hopkins (to JW), and Maryland Stem Cell Research Found (to JW). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
