Disease-on-the-dish Modeling of ELANE Start Codon Mutations in Human Severe Congenital Neutropenia

Disease-on-the-dish Modeling of ELANE Start Codon Mutations in Human Severe Congenital Neutropenia

Bibliographic Details
Main Author: Lee, Yarim
Language:English
Published: University of Cincinnati / OhioLINK 2021
Subjects:
Biology
Severe Congenital Neutropenia
neutropenia
Hematopoiesis
aggregphagy
protein aggregation
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=ucin1627668048604927
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spelling ndltd-OhioLink-oai-etd.ohiolink.edu-ucin16276680486049272021-10-16T05:25:21Z Disease-on-the-dish Modeling of ELANE Start Codon Mutations in Human Severe Congenital Neutropenia Lee, Yarim Biology Severe Congenital Neutropenia neutropenia Hematopoiesis aggregphagy protein aggregation Severe congenital neutropenia (SCN) is a heterozygous dominant autosomal hematopoietic disorder associated with differentiation arrest and cell death at the promyelocytic/myelocytic stages of granulopoietic differentiation, resulting in very low levels or absence of mature neutrophils in bone marrow and peripheral blood. Granulocyte-colony stimulating factor (G-CSF) is the cornerstone of therapy for this disease, however some mutations are associated with G-CSF resistance. Mutation in the ATG start codon of the ELANE gene interestingly gives rise to alternatively translated truncated peptides of neutrophil elastase (NE). The alternatively translated peptides are frequently misfolded which generates insoluble protein aggregates which induces apoptosis and cell death of granulocyte precursors. The cell death of ATG mutant promyelocytes is not due to unfolded protein response pathway mediated endoplasmic reticulum stress (UPR/ER-stress). The insoluble protein aggregates induce aggrephagy processes, as evidenced by the NE co-localization, with adaptor protein p62 in promyelocytes derived from ATG mutant patient’s iPSC and GTG knock-in iPSC lines. The ELANE ATG mutant granulopoiesis is insensitive to high concentration G-CSF therapy. We found that SERF1, a protein known to induce insoluble protein amyloid formation in neurons, is upregulated in ATG mutant promyelocytes. Downregulation of SERF1 rescues the survival of ATG mutant promyelocytes and myelocytes. Taken together, our data illustrates the mechanism of SCN associated with ATG mutations of ELANE and demonstrates the consequence of aggrephagy, which opens a new avenue for the therapy of G-CSF resistant SCN patients. 2021-10-04 English text University of Cincinnati / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=ucin1627668048604927 http://rave.ohiolink.edu/etdc/view?acc_num=ucin1627668048604927 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection NDLTD
language English
sources NDLTD
topic Biology
Severe Congenital Neutropenia
neutropenia
Hematopoiesis
aggregphagy
protein aggregation
spellingShingle Biology
Severe Congenital Neutropenia
neutropenia
Hematopoiesis
aggregphagy
protein aggregation
Lee, Yarim
Disease-on-the-dish Modeling of ELANE Start Codon Mutations in Human Severe Congenital Neutropenia
author Lee, Yarim
author_facet Lee, Yarim
author_sort Lee, Yarim
title Disease-on-the-dish Modeling of ELANE Start Codon Mutations in Human Severe Congenital Neutropenia
title_short Disease-on-the-dish Modeling of ELANE Start Codon Mutations in Human Severe Congenital Neutropenia
title_full Disease-on-the-dish Modeling of ELANE Start Codon Mutations in Human Severe Congenital Neutropenia
title_fullStr Disease-on-the-dish Modeling of ELANE Start Codon Mutations in Human Severe Congenital Neutropenia
title_full_unstemmed Disease-on-the-dish Modeling of ELANE Start Codon Mutations in Human Severe Congenital Neutropenia
title_sort disease-on-the-dish modeling of elane start codon mutations in human severe congenital neutropenia
publisher University of Cincinnati / OhioLINK
publishDate 2021
url http://rave.ohiolink.edu/etdc/view?acc_num=ucin1627668048604927
work_keys_str_mv AT leeyarim diseaseonthedishmodelingofelanestartcodonmutationsinhumanseverecongenitalneutropenia
_version_ 1719490098804817920

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