Full metadata record
DC Field | Value | Language |
---|---|---|
dc.contributor.author | 오기욱 | - |
dc.date.accessioned | 2022-05-31T07:08:58Z | - |
dc.date.available | 2022-05-31T07:08:58Z | - |
dc.date.issued | 2020-10 | - |
dc.identifier.citation | SCIENCE TRANSLATIONAL MEDICINE, v. 12, no. 566, article no. eaax3993 | en_US |
dc.identifier.issn | 1946-6234 | - |
dc.identifier.issn | 1946-6242 | - |
dc.identifier.uri | https://www.science.org/doi/10.1126/scitranslmed.aax3993 | - |
dc.identifier.uri | https://repository.hanyang.ac.kr/handle/20.500.11754/171260 | - |
dc.description.abstract | Dysregulation of calcium ion homeostasis and abnormal protein aggregation have been proposed as major pathogenic hallmarks underpinning selective degeneration of motor neurons in amyotrophic lateral sclerosis (ALS). Recently, mutations in annexin A11 (ANXA11), a gene encoding a Ca2+ -dependent phospholipid-binding protein, have been identified in familial and sporadic ALS. However, the physiological and pathophysiological roles of ANXA11 remain unknown. Here, we report functions of ANXA11 related to intracellular Ca2+ homeostasis and stress granule dynamics. We analyzed the exome sequences of 500 Korean patients with sALS and identified nine ANXA11 variants in 13 patients. The amino-terminal variants p.G38R and p.D40G within the low-complexity domain of ANXA11 enhanced aggregation propensity, whereas the carboxyl-terminal ANX domain variants p.H390P and p.R456H altered Ca2+ responses. Furthermore, all four variants in ANXA11 underwent abnormal phase separation to form droplets with aggregates and led to the alteration of the biophysical properties of ANXA11. These functional defects caused by ALS-linked variants induced alterations in both intracellular Ca2+ homeostasis and stress granule disassembly. We also revealed that p.G228Lfs*29 reduced ANXA11 expression and impaired Ca2+ homeostasis, as caused by missense variants. Ca2+-dependent interaction and coaggregation between ANXA11 and ALS-causative RNA-binding proteins, FUS and hnRNPA1, were observed in motor neuron cells and brain from a patient with ALS-FUS. The expression of ALS-linked ANXA11 variants in motor neuron cells caused cytoplasmic sequestration of endogenous FUS and triggered neuronal apoptosis. Together, our findings suggest that diseaseassociated ANXA11 mutations can contribute to ALS pathogenesis through toxic gain-of-function mechanisms involving abnormal protein aggregation. | en_US |
dc.description.sponsorship | This study was supported by the National Research Foundation, funded by the Ministry of Science (2018M3C7A1056512 to S.H.K., 2017M3C7A1025364 to K.-W.O., and 2017R1A6A3A04012311 to S.M.L.). | en_US |
dc.language.iso | en | en_US |
dc.publisher | AMER ASSOC ADVANCEMENT SCIENCE | en_US |
dc.subject | AMYOTROPHIC-LATERAL-SCLEROSIS | en_US |
dc.subject | ANNEXIN A11 | en_US |
dc.subject | SELECTIVE VULNERABILITY | en_US |
dc.subject | INTRACELLULAR CALCIUM | en_US |
dc.subject | PROTEIN | en_US |
dc.subject | MODEL | en_US |
dc.subject | NEURODEGENERATION | en_US |
dc.subject | ASSOCIATION | en_US |
dc.subject | RECEPTORS | en_US |
dc.subject | APOPTOSIS | en_US |
dc.title | ANXA11 mutations in ALS cause dysregulation of calcium homeostasis and stress granule dynamics | en_US |
dc.type | Article | en_US |
dc.relation.no | 566 | - |
dc.relation.volume | 12 | - |
dc.identifier.doi | 10.1126/scitranslmed.aax3993 | - |
dc.relation.page | 1-15 | - |
dc.relation.journal | SCIENCE TRANSLATIONAL MEDICINE | - |
dc.contributor.googleauthor | Nahm, Minyeop | - |
dc.contributor.googleauthor | Lim, Su Min | - |
dc.contributor.googleauthor | Kim, Young-Eun | - |
dc.contributor.googleauthor | Park, Jinseok | - |
dc.contributor.googleauthor | Noh, Min-Young | - |
dc.contributor.googleauthor | Lee, Sanggon | - |
dc.contributor.googleauthor | Roh, Ju Eun | - |
dc.contributor.googleauthor | Hwang, Sung-Min | - |
dc.contributor.googleauthor | Park, Chul-Kyu | - |
dc.contributor.googleauthor | Oh, Ki-Wook | - |
dc.relation.code | 2020050074 | - |
dc.sector.campus | S | - |
dc.sector.daehak | COLLEGE OF MEDICINE[S] | - |
dc.sector.department | DEPARTMENT OF MEDICINE | - |
dc.identifier.pid | kiwook-oh | - |
dc.identifier.orcid | https://orcid.org/0000-0001-6011-629X | - |
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.