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ALS-linked C9orf72 dipeptide repeats inhibit starvation-induced autophagy through modulating BCL2-BECN1 interaction.
Xu, Shiqiang; Ma, Qilian; Shen, Junwen; Li, Ningning; Sun, Shan; Wang, Nana; Chen, Yang; Dong, Chunsheng; Tam, Kin Yip; Prehn, Jochen H M; Wang, Hongfeng; Ying, Zheng.
Afiliación
  • Xu S; Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.
  • Ma Q; Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.
  • Shen J; Dept. of Physiology & Medical Physics and FUTURE-NEURO Research Centre, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland.
  • Li N; Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.
  • Sun S; Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.
  • Wang N; Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.
  • Chen Y; Faculty of Health Sciences, University of Macau, Taipa, Macau 999078, China.
  • Dong C; Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.
  • Tam KY; Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.
  • Prehn JHM; Insititutes of Biology and Medical Science, Soochow University, Suzhou 215123, China.
  • Wang H; Faculty of Health Sciences, University of Macau, Taipa, Macau 999078, China.
  • Ying Z; Dept. of Physiology & Medical Physics and FUTURE-NEURO Research Centre, Royal College of Surgeons in Ireland, Dublin D02 YN77, Ireland.
Acta Pharm Sin B ; 14(5): 2026-2038, 2024 May.
Article en En | MEDLINE | ID: mdl-38799643
ABSTRACT
Growing evidences indicate that dysfunction of autophagy contributes to the disease pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two neurodegenerative disorders. The GGGGCC·GGCCCC repeat RNA expansion in chromosome 9 open reading frame 72 (C9orf72) is the most genetic cause of both ALS and FTD. According to the previous studies, GGGGCC·GGCCCC repeat undergoes the unconventional repeat-associated non-ATG translation, which produces dipeptide repeat (DPR) proteins. Although there is a growing understanding that C9orf72 DPRs have a strong ability to harm neurons and induce C9orf72-linked ALS/FTD, whether these DPRs can affect autophagy remains unclear. In the present study, we find that poly-GR and poly-PR, two arginine-containing DPRs which display the most cytotoxic properties according to the previous studies, strongly inhibit starvation-induced autophagy. Moreover, our data indicate that arginine-rich DPRs enhance the interaction between BCL2 and BECN1/Beclin 1 by inhibiting BCL2 phosphorylation, therefore they can impair autophagic clearance of neurodegenerative disease-associated protein aggregates under starvation condition in cells. Importantly, our study not only highlights the role of C9orf72 DPR in autophagy dysfunction, but also provides novel insight that pharmacological intervention of autophagy using SW063058, a small molecule compound that can disrupt the interaction between BECN1 and BCL2, may reduce C9orf72 DPR-induced neurotoxicity.
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Texto completo: 1 Bases de datos: MEDLINE Idioma: En Revista: Acta Pharm Sin B Año: 2024 Tipo del documento: Article País de afiliación: China

Texto completo: 1 Bases de datos: MEDLINE Idioma: En Revista: Acta Pharm Sin B Año: 2024 Tipo del documento: Article País de afiliación: China