2025-11-21 トロント大学
<関連情報>
- https://www.utoronto.ca/news/study-uncovers-and-predicts-widespread-molecular-changes-als-brain-cells
- https://www.cell.com/cell-genomics/fulltext/S2666-979X(25)00263-0
深層学習に基づく代替ポリアデニル化機構の解読によるALS眼窩前頭皮質の単核トランスクリプトームアトラス Single-nucleus transcriptome atlas of orbitofrontal cortex in ALS with a deep learning-based decoding of alternative polyadenylation mechanisms
Paul M. McKeeve ∙ Aiden M. Sababi ∙ Raghav Sharma ∙ … ∙ Hani Goodarzi ∙ Gary D. Bader ∙ Janice Robertson
Cell Genomics Published:September 17, 2025
DOI:https://doi.org/10.1016/j.xgen.2025.101007
Graphical abstract
Highlights
- snRNA-seq atlas of orbitofrontal cortex in ALS identified cell-type-specific changes
- Comparative analyses with existing ALS datasets uncover shared molecular signatures
- Alternative polyadenylation is dysregulated across neuronal and glial cell types in ALS
- Deep learning model, APA-Net, decodes APA regulation from snRNA-seq data
Summary
Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are fatal neurodegenerative diseases sharing clinical and pathological features. Both involve complex neuron-glia interactions, but cell-type-specific alterations remain poorly defined. We performed single-nucleus RNA sequencing of the frontal cortex from C9orf72-related ALS (with and without FTLD) and sporadic ALS (sALS). Neurons showed prominent changes in mitochondrial function, protein homeostasis, and chromatin remodeling. Comparison with independent datasets from other cortical regions revealed consistent pathway alterations, including upregulation of STMN2 and NEFL across brain regions and subtypes. We further examined dysregulation of alternative polyadenylation (APA), an understudied post-transcriptional mechanism, uncovering cell-type-specific APA patterns. To investigate its regulation, we developed the alternative polyadenylation network (APA-Net), a multi-modal deep learning model integrating transcript sequences and RNA-binding protein (RBP) expression profiles to predict APA. This atlas advances our understanding of ALS/FTLD molecular pathology and provides a valuable resource for future mechanistic studies.
