PUBLICATION

Comparative Proteome Research in a Zebrafish Model for Vanishing White Matter Disease

Authors

Kim, D., Lee, Y.R., Choi, T.I., Kim, S.H., Kang, H.C., Kim, C.H., Lee, S.

ID

ZDB-PUB-210407-16

Date

2021

Source

International Journal of Molecular Sciences 22(5): (Journal)

Registered Authors

Kim, Cheol-Hee

Keywords

EIF2B, SLC1A4, Vanishing White Matter disease, comparative proteomics

MeSH Terms

Amino Acid Transport System ASC/genetics
Amino Acid Transport System ASC/metabolism*
Animals
Animals, Genetically Modified
Disease Models, Animal
Eukaryotic Initiation Factor-2B/deficiency
Eukaryotic Initiation Factor-2B/metabolism
Humans
Leukoencephalopathies/genetics
Leukoencephalopathies/metabolism*
Leukoencephalopathies/pathology
Proteome/genetics
Proteome/metabolism*
Proteomics
Zebrafish/genetics
Zebrafish/metabolism*
Zebrafish Proteins/genetics
Zebrafish Proteins/metabolism*

(all 18)

PubMed

33800130 Full text @ Int. J. Mol. Sci.

Abstract

Vanishing white matter (VWM) disease is a genetic leukodystrophy leading to severe neurological disease and early death. VWM is caused by bi-allelic mutations in any of the five genes encoding the subunits of the eukaryotic translation factor 2B (EIF2B). Previous studies have attempted to investigate the molecular mechanism of VWN by constructing models for each subunit of EIF2B that causes VWM disease. The underlying molecular mechanisms of the way in which mutations in EIF2B3 result in VWM are largely unknown. Based on our recent results, we generated an eif2b3 knockout (eif2b3^-/-) zebrafish model and performed quantitative proteomic analysis between the wild-type (WT) and eif2b3^-/- zebrafish, and identified 25 differentially expressed proteins. Four proteins were significantly upregulated, and 21 proteins were significantly downregulated in eif2b3^-/- zebrafish compared to WT. Lon protease and the neutral amino acid transporter SLC1A4 were significantly increased in eif2b3^-/- zebrafish, and crystallin proteins were significantly decreased. The differential expression of proteins was confirmed by the evaluation of mRNA levels in eif2b3^-/- zebrafish, using whole-mount in situ hybridization analysis. This study identified proteins which candidates as key regulators of the progression of VWN disease, using quantitative proteomic analysis in the first EIF2B3 animal model of VWN disease.

Genes / Markers

Marker	Marker Type	Name
abat	GENE	4-aminobutyrate aminotransferase
ass1	GENE	argininosuccinate synthase 1
atf4a	GENE	activating transcription factor 4a
atf6	GENE	activating transcription factor 6
cad	GENE	carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase
crybb1	GENE	crystallin, beta B1
dhtkd1	GENE	dehydrogenase E1 and transketolase domain containing 1
eif2b3	GENE	eukaryotic translation initiation factor 2B, subunit 3 gamma
lonp1	GENE	lon peptidase 1, mitochondrial
mbpa	GENE	myelin basic protein a

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Figures

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Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
abat	eif2b3^{ck156a/ck156a}	standard conditions	Protruding-mouth	midbrain hindbrain boundary	ISH	Figure 4
abat	WT	standard conditions	Protruding-mouth	midbrain hindbrain boundary	ISH	Figure 4
ass1	eif2b3^{ck156a/ck156a}	standard conditions	Protruding-mouth	midbrain hindbrain boundary	ISH	Figure 4
ass1	WT	standard conditions	Protruding-mouth	midbrain hindbrain boundary	ISH	Figure 4
atf4a	eif2b3^{ck156a/ck156a}	standard conditions	Protruding-mouth	midbrain hindbrain boundary	ISH	Fig. S3
atf6	eif2b3^{ck156a/ck156a}	standard conditions	Protruding-mouth	midbrain hindbrain boundary	ISH	Fig. S3
cad	eif2b3^{ck156a/ck156a}	standard conditions	Protruding-mouth	midbrain hindbrain boundary	ISH	Figure 4
cad	WT	standard conditions	Protruding-mouth	midbrain hindbrain boundary	ISH	Figure 4
crybb1	eif2b3^{ck156a/ck156a}	standard conditions	Protruding-mouth	lens	ISH	Fig. S4
crybb1	WT	standard conditions	Protruding-mouth	lens	ISH	Fig. S4

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
eif2b3^{ck156a/ck156a}	standard conditions	Long-pec	midbrain hindbrain boundary xbp1 expression increased amount, abnormal	Fig. S2
eif2b3^{ck156a/ck156a}	standard conditions	Protruding-mouth	central nervous system glial cell (sensu Vertebrata) olig2 expression decreased amount, abnormal	Figure 1
eif2b3^{ck156a/ck156a}	standard conditions	Protruding-mouth	lens decreased size, abnormal	Fig. S4
eif2b3^{ck156a/ck156a}	standard conditions	Protruding-mouth	midbrain hindbrain boundary abat expression increased amount, abnormal	Figure 4
eif2b3^{ck156a/ck156a}	standard conditions	Protruding-mouth	midbrain hindbrain boundary ass1 expression decreased amount, abnormal	Figure 4
eif2b3^{ck156a/ck156a}	standard conditions	Protruding-mouth	midbrain hindbrain boundary atf4a expression increased amount, abnormal	Fig. S3
eif2b3^{ck156a/ck156a}	standard conditions	Protruding-mouth	midbrain hindbrain boundary atf6 expression increased amount, abnormal	Fig. S3
eif2b3^{ck156a/ck156a}	standard conditions	Protruding-mouth	midbrain hindbrain boundary cad expression decreased amount, abnormal	Figure 4
eif2b3^{ck156a/ck156a}	standard conditions	Protruding-mouth	midbrain hindbrain boundary lonp1 expression increased amount, abnormal	Figure 4
eif2b3^{ck156a/ck156a}	standard conditions	Protruding-mouth	midbrain hindbrain boundary psat1 expression increased amount, abnormal	Fig. S2

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
ck5Tg	Tg(mbpa:GAP-GFP)	Transgenic Insertion
ck156a		Small Deletion	eif2b3

Human Disease / Model

Human Disease	Fish	Conditions	Evidence
leukoencephalopathy with vanishing white matter	eif2b3^{ck156a/ck156a}	standard conditions	TAS

Sequence Targeting Reagents

Fish

Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
GFP	EFG	GFP

Mapping

Kim et al., 2021 ZDB-PUB-210407-16 PMID:33800130

Comparative Proteome Research in a Zebrafish Model for Vanishing White Matter Disease

Kim et al., 2021

ZDB-PUB-210407-16
PMID:33800130