首页|ALS-linked C9orf72 dipeptide repeats inhibit starvation-induced autophagy through modulating BCL2-BECN1 interaction

ALS-linked C9orf72 dipeptide repeats inhibit starvation-induced autophagy through modulating BCL2-BECN1 interaction

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Growing evidences indicate that dysfunction of autophagy contributes to the disease patho-genesis of amyotrophic lateral sclerosis(ALS)and frontotemporal dementia(FTD),two neurodegenera-tive 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,there-fore they can impair autophagic clearance of neurodegenerative disease-associated protein aggregates un-der 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.

Amyotrophic lateral sclerosisFrontotemporal dementiaC9orf72AutophagyBCL2BECN1/Beclin 1Dipeptide repeatNeurodegeneration

Shiqiang Xu、Qilian Ma、Junwen Shen、Ningning Li、Shan Sun、Nana Wang、Yang Chen、Chunsheng Dong、Kin Yip Tam、Jochen H.M.Prehn、Hongfeng Wang、Zheng Ying

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Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences,Soochow University,Suzhou 215123,China

Dept.of Physiology & Medical Physics and FUTURE-NEURO Research Centre,Royal College of Surgeons in Ireland,Dublin D02 YN77,Ireland

Faculty of Health Sciences,University of Macau,Taipa,Macau 999078,China

Insititutes of Biology and Medical Science,Soochow University,Suzhou 215123,China

MOE Key Laboratory of Geriatric Diseases and Immunology,College of Pharmaceutical Sciences,Suzhou Medical College of Soochow University,Suzhou 215123,China

Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development,Soochow University,Suzhou 215123,China

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国家自然科学基金国家自然科学基金国家自然科学基金Jiangsu Key Laboratory of Neuropsychiatric Diseases,Chinaa Key Project of Natural Science Foundation of Jiangsu Provincial Higher Education Institutions,ChinaInterdisciplinary Basic Frontier Innovation Program of Suzhou Medical College of Soochow University,ChinaSuzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases江苏高校优势学科建设工程项目Science Foundation IrelandScience Foundation IrelandRCSI International StAR Ph.D.scholarshipPostgraduate Research & Practice Innovation Program of Jiangsu ProvinceScience and Technology Development Fund,Macau SAR,ChinaUniversity of Macau,China

820220223237101882071274BM201300323KJA310005MP1320282317/COEN/347417/JPND/34550062/2021/AMYRG2022-00171-FHS

2024

10.1016/j.apsb.2024.02.004

药学学报(英文版)

药学学报(英文版)

CSTPCD
ISSN：
年,卷(期)：2024.14(5)
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