C9ORF72 dipeptide repeat proteins disrupt formation of GEM bodies and induce aberrant accumulation of survival of motor neuron protein
C9ORF72 dipeptide repeat proteins disrupt formation of GEM bodies and induce aberrant accumulation of survival of motor neuron protein
Abstract A GGGGCC repeat expansion in the C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS), a devastating motor neuron disease. In the neurons of ALS patients, dipeptide repeat proteins (DPRs) are produced from repeat-containing RNAs by an unconventional form of translation, and some of these proteins, especially those containing poly(glycine-arginine) and poly(proline-arginine), are toxic to neurons. Gemini of coiled bodies (GEMs) are nuclear structures that harbor survival of motor neuron (SMN) protein, and SMN is essential for the assembly of U-rich small nuclear ribonucleoproteins (snRNPs) that are central for splicing. We previously reported that GEMs are lost and that snRNP biogenesis is misregulated in the motor neurons of ALS patients. Here we show that DPRs interfere with GEM formation and proper SMN localization in HeLa cells and iPSC-derived motor neurons from an ALS patient with the C9ORF72 mutation. The accumulation of poly(glycine-arginine) markedly reduced the number of GEMs and caused the formation of aberrant cytoplasmic RNA granules that sequestered SMN. These findings indicate the functional impairment of SMN in motor neurons expressing DPRs and may provide a mechanism to explain the vulnerability of motor neurons of C9ORF72-ALS patients.
Yokogawa Minnie、Onodera Kazunari、Hattori Mitsuharu、Okano Hideyuki、Tsuiji Hitomi、Nakagawa Ikuma、Okada Yohei、Inoue Haruhisa、Kato Yuma
Department of Biomedical Science, Graduate School of Pharmaceutical Sciences, Nagoya City UniversityDepartment of Neurology, Aichi Medical University School of MedicineDepartment of Biomedical Science, Graduate School of Pharmaceutical Sciences, Nagoya City UniversityDepartment of Physiology, Keio University School of MedicineDepartment of Biomedical Science, Graduate School of Pharmaceutical Sciences, Nagoya City UniversityDepartment of Biomedical Science, Graduate School of Pharmaceutical Sciences, Nagoya City UniversityDepartment of Neurology, Aichi Medical University School of MedicineCenter for iPS Cell Research and Application, Kyoto University||iPSC-Based Drug Discovery and Development Team, RIKEN BioResource Research Center (BRC)||Medical-risk Avoidance based on iPS Cells Team, RIKEN Center for Advanced Intelligence Project (AIP)Department of Biomedical Science, Graduate School of Pharmaceutical Sciences, Nagoya City University
神经病学、精神病学基础医学分子生物学
ALSC9ORF72SMNiPSCsdipeptide repeat proteins
Yokogawa Minnie,Onodera Kazunari,Hattori Mitsuharu,Okano Hideyuki,Tsuiji Hitomi,Nakagawa Ikuma,Okada Yohei,Inoue Haruhisa,Kato Yuma.C9ORF72 dipeptide repeat proteins disrupt formation of GEM bodies and induce aberrant accumulation of survival of motor neuron protein[EB/OL].(2025-03-28)[2025-05-06].https://www.biorxiv.org/content/10.1101/2021.03.24.436890.点此复制
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