한빛사논문
- 조회600
Elaine Piriea,1, Chang-ki Ohb,c,d,1, Xu Zhangb,c,d, Xuemei Hanb,c,d, Piotr Cieplake, Henry R. Scottb,c,d, Amanda K. Dealb,c,d, Swagata Ghatakb,c,d, Fernando J. Martineza, Gene W. Yeoa, John R. Yates IIIb,c,d, Tomohiro Nakamurab,c,d,2, and Stuart A. Liptonb,c,d,f,2
aDepartment of Cellular and Molecular Medicine and Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, CA 92093; bDepartment of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037; cDepartment of Neuroscience, The Scripps Research Institute, La Jolla, CA 92037; dNeuroscience Translational Center, The Scripps Research Institute, La Jolla, CA 92037; eBioinformatics and Structural Biology Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037; and fDepartment of Neurosciences, University of California San Diego School of Medicine, La Jolla, CA 92093
1E.P. and C.-k.O. contributed equally to this work.
2To whom correspondence may be addressed.
Abstract
Rare genetic mutations result in aggregation and spreading of cognate proteins in neurodegenerative disorders; however, in the absence of mutation (i.e., in the vast majority of “sporadic” cases), mechanisms for protein misfolding/aggregation remain largely unknown. Here, we show environmentally induced nitrosative stress triggers protein aggregation and cell-to-cell spread. In patient brains with amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD), aggregation of the RNA-binding protein TDP-43 constitutes a major component of aberrant cytoplasmic inclusions. We identify a pathological signaling cascade whereby reactive nitrogen species cause S-nitrosylation of TDP-43 (forming SNO-TDP-43) to facilitate disulfide linkage and consequent TDP-43 aggregation. Similar pathological SNO-TDP-43 levels occur in postmortem human FTD/ALS brains and in cell-based models, including human-induced pluripotent stem cell (hiPSC)-derived neurons. Aggregated TDP-43 triggers additional nitrosative stress, representing positive feed forward leading to further SNO-TDP-43 formation and disulfide-linked oligomerization/aggregation. Critically, we show that these redox reactions facilitate cell spreading in vivo and interfere with the TDP-43 RNA-binding activity, affecting SNMT1 and phospho-(p)CREB levels, thus contributing to neuronal damage in ALS/FTD disorders.
TDP-43 proteinopathy, S-nitrosylation, aggregation, spread
논문정보
- Research article
- 2021년 03월 (BRIC 등록일 2021-04-07)
- 국외 연구진
- 생명과학 > 세포생물학
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