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npc2-Deficient Zebrafish Reproduce Neurological and Inflammatory Symptoms of Niemann-Pick Type C Disease

Niemann-Pick type C (NPC) disease is an autosomal recessive lysosomal storage disease that is caused by a mutation of the NPC1 or NPC2 gene, in which un-esterified cholesterol and sphingolipids accumulate mainly in the liver, spleen, and brain. Abnormal lysosomal storage leads to cell damage, neurol...

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Autores principales: Wiweger, Malgorzata, Majewski, Lukasz, Adamek-Urbanska, Dobrochna, Wasilewska, Iga, Kuznicki, Jacek
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111220/
https://www.ncbi.nlm.nih.gov/pubmed/33986646
http://dx.doi.org/10.3389/fncel.2021.647860
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author Wiweger, Malgorzata
Majewski, Lukasz
Adamek-Urbanska, Dobrochna
Wasilewska, Iga
Kuznicki, Jacek
author_facet Wiweger, Malgorzata
Majewski, Lukasz
Adamek-Urbanska, Dobrochna
Wasilewska, Iga
Kuznicki, Jacek
author_sort Wiweger, Malgorzata
collection PubMed
description Niemann-Pick type C (NPC) disease is an autosomal recessive lysosomal storage disease that is caused by a mutation of the NPC1 or NPC2 gene, in which un-esterified cholesterol and sphingolipids accumulate mainly in the liver, spleen, and brain. Abnormal lysosomal storage leads to cell damage, neurological problems, and premature death. The time of onset and severity of symptoms of NPC disease are highly variable. The molecular mechanisms that are responsible for NPC disease pathology are far from being understood. The present study generated and characterized a zebrafish mutant that lacks Npc2 protein that may be useful for studies at the organismal, cellular, and molecular levels and both small-scale and high-throughput screens. Using CRISPR/Cas9 technology, we knocked out the zebrafish homolog of NPC2. Five-day-old npc2 mutants were morphologically indistinguishable from wildtype larvae. We found that live npc2(–/–) larvae exhibited stronger Nile blue staining. The npc2(–/–) larvae exhibited low mobility and a high anxiety-related response. These behavioral changes correlated with downregulation of the mcu (mitochondrial calcium uniporter) gene, ppp3ca (calcineurin) gene, and genes that are involved in myelination (mbp and mpz). Histological analysis of adult npc2(–/–) zebrafish revealed that pathological changes in the nervous system, kidney, liver, and pancreas correlated with inflammatory responses (i.e., the upregulation of il1, nfκβ, and mpeg; i.e., hallmarks of NPC disease). These findings suggest that the npc2 mutant zebrafish may be a model of NPC disease.
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spelling pubmed-81112202021-05-12 npc2-Deficient Zebrafish Reproduce Neurological and Inflammatory Symptoms of Niemann-Pick Type C Disease Wiweger, Malgorzata Majewski, Lukasz Adamek-Urbanska, Dobrochna Wasilewska, Iga Kuznicki, Jacek Front Cell Neurosci Neuroscience Niemann-Pick type C (NPC) disease is an autosomal recessive lysosomal storage disease that is caused by a mutation of the NPC1 or NPC2 gene, in which un-esterified cholesterol and sphingolipids accumulate mainly in the liver, spleen, and brain. Abnormal lysosomal storage leads to cell damage, neurological problems, and premature death. The time of onset and severity of symptoms of NPC disease are highly variable. The molecular mechanisms that are responsible for NPC disease pathology are far from being understood. The present study generated and characterized a zebrafish mutant that lacks Npc2 protein that may be useful for studies at the organismal, cellular, and molecular levels and both small-scale and high-throughput screens. Using CRISPR/Cas9 technology, we knocked out the zebrafish homolog of NPC2. Five-day-old npc2 mutants were morphologically indistinguishable from wildtype larvae. We found that live npc2(–/–) larvae exhibited stronger Nile blue staining. The npc2(–/–) larvae exhibited low mobility and a high anxiety-related response. These behavioral changes correlated with downregulation of the mcu (mitochondrial calcium uniporter) gene, ppp3ca (calcineurin) gene, and genes that are involved in myelination (mbp and mpz). Histological analysis of adult npc2(–/–) zebrafish revealed that pathological changes in the nervous system, kidney, liver, and pancreas correlated with inflammatory responses (i.e., the upregulation of il1, nfκβ, and mpeg; i.e., hallmarks of NPC disease). These findings suggest that the npc2 mutant zebrafish may be a model of NPC disease. Frontiers Media S.A. 2021-04-27 /pmc/articles/PMC8111220/ /pubmed/33986646 http://dx.doi.org/10.3389/fncel.2021.647860 Text en Copyright © 2021 Wiweger, Majewski, Adamek-Urbanska, Wasilewska and Kuznicki. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Wiweger, Malgorzata
Majewski, Lukasz
Adamek-Urbanska, Dobrochna
Wasilewska, Iga
Kuznicki, Jacek
npc2-Deficient Zebrafish Reproduce Neurological and Inflammatory Symptoms of Niemann-Pick Type C Disease
title npc2-Deficient Zebrafish Reproduce Neurological and Inflammatory Symptoms of Niemann-Pick Type C Disease
title_full npc2-Deficient Zebrafish Reproduce Neurological and Inflammatory Symptoms of Niemann-Pick Type C Disease
title_fullStr npc2-Deficient Zebrafish Reproduce Neurological and Inflammatory Symptoms of Niemann-Pick Type C Disease
title_full_unstemmed npc2-Deficient Zebrafish Reproduce Neurological and Inflammatory Symptoms of Niemann-Pick Type C Disease
title_short npc2-Deficient Zebrafish Reproduce Neurological and Inflammatory Symptoms of Niemann-Pick Type C Disease
title_sort npc2-deficient zebrafish reproduce neurological and inflammatory symptoms of niemann-pick type c disease
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111220/
https://www.ncbi.nlm.nih.gov/pubmed/33986646
http://dx.doi.org/10.3389/fncel.2021.647860
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