Dysregulated synaptic gene expression in oligodendrocytes of spinal and bulbar muscular atrophy
Madoka Iida, Kentaro Sahashi, Tomoki Hirunagi, Kenji Sakakibara, Kentaro Maeda, Yohei Iguchi, Jiayi Li, Yosuke Ogura, Masaki Iizuka, Tomohiro Akashi, Kunihiko Hinohara, Shouta Sugio, Hiroaki Wake, Masahiro Nakatochi, Masahisa Katsuno
Madoka Iida, Kentaro Sahashi, Tomoki Hirunagi, Kenji Sakakibara, Kentaro Maeda, Yohei Iguchi, Jiayi Li, Yosuke Ogura, Masaki Iizuka, Tomohiro Akashi, Kunihiko Hinohara, Shouta Sugio, Hiroaki Wake, Masahiro Nakatochi, Masahisa Katsuno
View: Text | PDF
Research Article Cell biology Neuroscience

Dysregulated synaptic gene expression in oligodendrocytes of spinal and bulbar muscular atrophy

Abstract

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by an expanded CAG repeat in the androgen receptor (AR) gene. To elucidate the cell type–specific temporal gene expression in SBMA, we performed single-nucleus RNA sequencing on the spinal cords of an SBMA mouse model (AR-97Q). Among all cell types, oligodendrocytes had the highest number of differentially expressed genes before disease onset. Analysis of oligodendrocyte clusters suggested that pathways associated with cation channels and synaptic function were activated before disease onset, with increased output from oligodendrocytes to neurons in AR-97Q mice compared with wild-type mice. These changes in the early stages were abrogated at the advanced stages. An oligodendrocyte model of SBMA showed phenotypes similar to those of AR-97Q mice at early stages, such as increased transcriptional changes in synapse organization, and Ca2+ imaging of oligodendrocytes in AR-97Q mice revealed the increased Ca2+ responses. A coculture system of primary rat oligodendrocytes and neurons revealed that the mutant AR in oligodendrocytes affected the activity and synchronization of neurons. These findings suggest that dysregulated cell-to-cell communication plays a critical role in early SBMA pathology and that synaptic or ion channel–related proteins, such as contactin associated protein 2 (Cntnap2) and NALCN channel auxiliary factor 1 (Fam155a), are potential therapeutic targets for SBMA.

Authors

Madoka Iida, Kentaro Sahashi, Tomoki Hirunagi, Kenji Sakakibara, Kentaro Maeda, Yohei Iguchi, Jiayi Li, Yosuke Ogura, Masaki Iizuka, Tomohiro Akashi, Kunihiko Hinohara, Shouta Sugio, Hiroaki Wake, Masahiro Nakatochi, Masahisa Katsuno

×

Figure 1

SnRNA-Seq of the spinal cords from AR-97Q and wild-type mice reveals cell type–specific differences.

Options: View larger image (or click on image) Download as PowerPoint
SnRNA-Seq of the spinal cords from AR-97Q and wild-type mice reveals cel...
(A) A scheme showing the stages of disease in AR-97Q mice. (B) t-Distributed stochastic neighbor embedding (t-SNE) and uniform manifold approximation and projection (UMAP) plots of 54,456 nuclei from the spinal cords of all mice used in this experiment. OL, Oligodendrocytes; OPC, Oligodendrocyte precursor cell. (C) Proportion of the 9 cell types of each sample. (D–G) Number of DEGs in each cell type in AR-97Q mice and wild-type mice. Adjusted P < 0.05, absolute log2 fold-change (|log2FC|) ≥ 0.20 for 3 weeks of age (D) and |log2FC| ≥ 0.40 for 6, 9, and 13 weeks of age (E–G). (H) t-SNE plot of nuclei color-coded by each sample (left) and t-SNE plots of nuclei comparing AR-97Q mice with wild-type mice at 4 different disease stages (right). A, AR-97Q mice; W, wild-type mice (ex. A3 indicates AR-97Q mice at 3 weeks); N = 4 mice for each sample.