Effect on cell survival and cytoophidium assembly of the adRP-10-related IMPDH1 missense mutation Asp226Asn

doi:10.3389/fcell.2023.1234592

	Effect on cell survival and cytoophidium assembly of the adRP-10-related IMPDH1 missense mutation Asp226Asn
	Keppeke, Gerson Dierley 1,2; Chang, Chia-Chun3,4 ; Zhang, Ziheng3 ; Liu, Ji-Long3,5
	2023-09-04
发表期刊	FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY (IF:4.6[JCR-2023],5.2[5-Year])
ISSN	2296-634X
卷号	11
发表状态	已发表
DOI	10.3389/fcell.2023.1234592
摘要	Introduction: Inosine monophosphate dehydrogenase 1 (IMPDH1) is a critical enzyme in the retina, essential for the correct functioning of photoreceptor cells. Mutations in IMPDH1 have been linked to autosomal dominant retinitis pigmentosa subtype 10 (adRP-10), a genetic eye disorder. Some of these mutations such as the Asp226Asn (D226N) lead to the assembly of large filamentous structures termed cytoophidia. D226N also gives IMPDH1 resistance to feedback inhibition by GDP/GTP. This study aims to emulate the adRP-10 condition with a long-term expression of IMPDH1-D226N in vitro and explore cytoophidium assembly and cell survival. We also assessed whether the introduction of an additional mutation (Y12C) to disrupt the cytoophidium has an attenuating effect on the toxicity caused by the D226N mutation.Results: Expression of IMPDH1-D226N in HEp-2 cells resulted in cytoophidium assembly in & SIM;70% of the cells, but the presence of the Y12C mutation disrupted the filaments. Long-term cell survival was significantly affected by the presence of the D226N mutation, with a decrease of & SIM;40% in the cells expressing IMPDH1-D226N when compared to IMPDH1-WT; however, survival was significantly recovered in IMPDH1-Y12C/D226N, with only a & SIM;10% decrease when compared to IMPDH1-WT. On the other hand, the IMPDH1 expression level in the D226N-positive cells was <30% of that of the IMPDH1-WT-positive cells and only slightly higher in the Y12C/D226N, suggesting that although cell survival in Y12C/D226N was recovered, higher expression levels of the mutated IMPDH1 were not tolerated by the cells in the long term.Conclusion: The IMPDH1-D226N effect on photoreceptor cell survival may be the result of a sum of problems: nucleotide unbalance plus a toxic long-life cytoophidium, supported by the observation that by introducing Y12C in IMPDH1 the cytoophidium was disrupted and cell survival significantly recovered, but not the sensibility to GDP/GTP regulation since higher expression levels of IMPDH1-D226N were not tolerated.
关键词	IMPDH1 cytoophidium apoptosis cell survival autosomal dominant retinitis pigmentosa subtype 10 (adRP-10) missense mutation Asp226Asn rs121912550
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收录类别	SCI
语种	英语
资助项目	Sao Paulo Government Agency FAPESP (Sao Paulo State Research Foundation)[2017/20745-1] ; United Kingdom Medical Research Council["MC_UU_12021/3","MC_ U137788471"]
WOS研究方向	Cell Biology ; Developmental Biology
WOS类目	Cell Biology ; Developmental Biology
WOS记录号	WOS:001068586800001
出版者	FRONTIERS MEDIA SA
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/337711
专题	生命科学与技术学院生命科学与技术学院_PI研究组_刘冀珑组生命科学与技术学院_博士生
通讯作者	Keppeke, Gerson Dierley; Liu, Ji-Long
作者单位	1.Univ Catolica Norte, Fac Med, Dept Ciencias Biomed, Coquimbo, Chile 2.Univ Fed Sao Paulo, Escola Paulista Med, Rheumatol Div, Sao Paulo, Brazil 3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China 4.Natl Taiwan Univ, Inst Biotechnol, Taipei, Taiwan 5.Univ Oxford, Dept Physiol Anat & Genet, Oxford, England
通讯作者单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Keppeke, Gerson Dierley,Chang, Chia-Chun,Zhang, Ziheng,et al. Effect on cell survival and cytoophidium assembly of the adRP-10-related IMPDH1 missense mutation Asp226Asn[J]. FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY,2023,11.
APA	Keppeke, Gerson Dierley,Chang, Chia-Chun,Zhang, Ziheng,&Liu, Ji-Long.(2023).Effect on cell survival and cytoophidium assembly of the adRP-10-related IMPDH1 missense mutation Asp226Asn.FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY,11.
MLA	Keppeke, Gerson Dierley,et al."Effect on cell survival and cytoophidium assembly of the adRP-10-related IMPDH1 missense mutation Asp226Asn".FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY 11(2023).