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Lim, Chunghun
Neurogenetics & Ribonomics Laboratory (The Lim Lab)
Research Interests
  • Ribosome Biology, Translation, Neurodegeneration, Behavioral Genetics

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ZNF598 co-translationally titrates poly(GR) protein implicated in the pathogenesis of C9ORF72-associated ALS/FTD

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dc.contributor.author Park, Jumin ko
dc.contributor.author Lee, Jongbo ko
dc.contributor.author Kim, Ji-hyung ko
dc.contributor.author Lee, Jongbin ko
dc.contributor.author Park, Heeju ko
dc.contributor.author Lim, Chunghun ko
dc.date.available 2021-10-07T07:56:49Z -
dc.date.created 2021-10-03 ko
dc.date.issued 2021-09 ko
dc.identifier.citation NUCLEIC ACIDS RESEARCH ko
dc.identifier.issn 0305-1048 ko
dc.identifier.uri https://scholarworks.unist.ac.kr/handle/201301/54064 -
dc.description.abstract C9ORF72-derived dipeptide repeat proteins have emerged as the pathogenic cause of neurodegeneration in amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). However, the mechanisms underlying their expression are not fully understood. Here, we demonstrate that ZNF598, the rate-limiting factor for ribosome-associated quality control (RQC), co-translationally titrates the expression of C9ORF72-derived poly(GR) protein. A Drosophila genetic screen identified key RQC factors as potent modifiers of poly(GR)-induced neurodegeneration. ZNF598 overexpression in human neuroblastoma cells inhibited the nuclear accumulation of poly(GR) protein and decreased its cytotoxicity, whereas ZNF598 deletion had opposing effects. Poly(GR)-encoding sequences in the reporter RNAs caused translational stalling and generated ribosome-associated translation products, sharing molecular signatures with canonical RQC substrates. Furthermore, ZNF598 and listerin 1, the RQC E3 ubiquitin-protein ligase, promoted poly(GR) degradation via the ubiquitin-proteasome pathway. An ALS-relevant ZNF598R69C mutant displayed loss-of-function effects on poly(GR) expression, as well as on general RQC. Moreover, RQC function was impaired in C9-ALS patient-derived neurons, whereas lentiviral overexpression of ZNF598 lowered their poly(GR) expression and suppressed proapoptotic caspase-3 activation. Taken together, we propose that an adaptive nature of the RQC-relevant ZNF598 activity allows the co-translational surveillance to cope with the atypical expression of pathogenic poly(GR) protein, thereby acquiring a neuroprotective function in C9-ALS/FTD. ko
dc.language 영어 ko
dc.publisher Oxford University Press ko
dc.title ZNF598 co-translationally titrates poly(GR) protein implicated in the pathogenesis of C9ORF72-associated ALS/FTD ko
dc.type ARTICLE ko
dc.type.rims ART ko
dc.identifier.doi 10.1093/nar/gkab834 ko
dc.identifier.url https://academic.oup.com/nar/advance-article/doi/10.1093/nar/gkab834/6374173 ko
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