| RRC ID |
58485
|
| 著者 |
Onodera K, Shimojo D, Ishihara Y, Yano M, Miya F, Banno H, Kuzumaki N, Ito T, Okada R, de Araújo Herculano B, Ohyama M, Yoshida M, Tsunoda T, Katsuno M, Doyu M, Sobue G, Okano H, Okada Y.
|
| タイトル |
Unveiling synapse pathology in spinal bulbar muscular atrophy by genome-wide transcriptome analysis of purified motor neurons derived from disease specific iPSCs.
|
| ジャーナル |
Mol Brain
|
| Abstract |
Spinal bulbar muscular atrophy (SBMA) is an adult-onset, slowly progressive motor neuron disease caused by abnormal CAG repeat expansion in the androgen receptor (AR) gene. Although ligand (testosterone)-dependent mutant AR aggregation has been shown to play important roles in motor neuronal degeneration by the analyses of transgenic mice models and in vitro cell culture models, the underlying disease mechanisms remain to be fully elucidated because of the discrepancy between model mice and SBMA patients. Thus, novel human disease models that recapitulate SBMA patients' pathology more accurately are required for more precise pathophysiological analysis and the development of novel therapeutics. Here, we established disease specific iPSCs from four SBMA patients, and differentiated them into spinal motor neurons. To investigate motor neuron specific pathology, we purified iPSC-derived motor neurons using flow cytometry and cell sorting based on the motor neuron specific reporter, HB9e438::Venus, and proceeded to the genome-wide transcriptome analysis by RNA sequences. The results revealed the involvement of the pathology associated with synapses, epigenetics, and endoplasmic reticulum (ER) in SBMA. Notably, we demonstrated the involvement of the neuromuscular synapse via significant upregulation of Synaptotagmin, R-Spondin2 (RSPO2), and WNT ligands in motor neurons derived from SBMA patients, which are known to be associated with neuromuscular junction (NMJ) formation and acetylcholine receptor (AChR) clustering. These aberrant gene expression in neuromuscular synapses might represent a novel therapeutic target for SBMA.
|
| 巻・号 |
13(1)
|
| ページ |
18
|
| 公開日 |
2020-2-19
|
| DOI |
10.1186/s13041-020-0561-1
|
| PII |
10.1186/s13041-020-0561-1
|
| PMID |
32070397
|
| PMC |
PMC7029484
|
| MeSH |
Adult
Animals
Cells, Cultured
Cellular Reprogramming Techniques
Fibroblasts
Gene Expression Profiling*
Gene Ontology
Genome-Wide Association Study
Humans
Induced Pluripotent Stem Cells / cytology*
Male
Mice
Mice, Transgenic
Middle Aged
Motor Neurons
Muscular Atrophy, Spinal / genetics
Muscular Atrophy, Spinal / pathology*
Neurogenesis
Synapses / pathology*
Transcription Factors / physiology
Trinucleotide Repeat Expansion
Young Adult
|
| IF |
4.686
|
| 引用数 |
1
|
| リソース情報 |
| 遺伝子材料 |
pCAG-HIVgp (RDB04394)
pCMV-VSV-G-RSV-Rev (RDB04393) |
