PUBLICATION

Tau accumulation is cleared by the induced expression of VCP via autophagy

Authors

Giong, H.K., Hyeon, S.J., Lee, J.G., Cho, H.J., Park, U., Stein, T.D., Lee, J., Yu, K., Ryu, H., Lee, J.S.

ID

ZDB-PUB-240925-2

Date

2024

Source

Acta Neuropathologica 148: 4646 (Journal)

Registered Authors

Cho, Hyun-Ju, Giong, Hoi-Khoanh, Lee, Jae-Geun, Lee, Jeong-Soo

Keywords

Autophagy, Tau clearance, Tau-overexpressing animal models, VCP/p97

MeSH Terms

Mice
Humans
Tauopathies/genetics
Tauopathies/metabolism
Tauopathies/pathology
Zebrafish*
tau Proteins*/genetics
tau Proteins*/metabolism
Animals, Genetically Modified*
Valosin Containing Protein*/genetics
Valosin Containing Protein*/metabolism
Brain/metabolism
Brain/pathology
Autophagy*/physiology
Alzheimer Disease/genetics
Alzheimer Disease/metabolism
Alzheimer Disease/pathology
Disease Models, Animal
Mice, Transgenic
Animals

(all 20)

PubMed

39316141 Full text @ Acta Neuropathol.

Abstract

Tauopathy, including frontotemporal lobar dementia and Alzheimer's disease, describes a class of neurodegenerative diseases characterized by the aberrant accumulation of Tau protein due to defects in proteostasis. Upon generating and characterizing a stable transgenic zebrafish that expresses the human TAU^P301L mutant in a neuron-specific manner, we found that accumulating Tau protein was efficiently cleared via an enhanced autophagy activity despite constant Tau mRNA expression; apparent tauopathy-like phenotypes were revealed only when the autophagy was genetically or chemically inhibited. We performed RNA-seq analysis, genetic knockdown, and rescue experiments with clinically relevant point mutations of valosin-containing protein (VCP), and showed that induced expression of VCP, an essential cytosolic chaperone for the protein quality system, was a key factor for Tau degradation via its facilitation of the autophagy flux. This novel function of VCP in Tau clearance was further confirmed in a tauopathy mouse model where VCP overexpression significantly decreased the level of phosphorylated and oligomeric/aggregate Tau and rescued Tau-induced cognitive behavioral phenotypes, which were reversed when the autophagy was blocked. Importantly, VCP expression in the brains of human Alzheimer's disease patients was severely downregulated, consistent with its proposed role in Tau clearance. Taken together, these results suggest that enhancing the expression and activity of VCP in a spatiotemporal manner to facilitate the autophagy pathway is a potential therapeutic approach for treating tauopathy.

Genes / Markers

Figures

Show all Figures

Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
atg5	krb5Tg/krb5Tg	standard conditions	Long-pec	whole organism	WB	Fig. 2
atg5	krb5Tg/krb5Tg + MO1-atg5	standard conditions	Long-pec	whole organism	WB	Fig. 2
atg5	WT	standard conditions	Long-pec	whole organism	WB	Fig. 2
atg5	WT + MO1-atg5	standard conditions	Long-pec	whole organism	WB	Fig. 2
il6	krb5Tg	standard conditions	Long-pec	whole organism	RTPCR	Fig. 1
il6	krb5Tg	standard conditions	Prim-5	whole organism	RTPCR	Fig. 1
il6	krb5Tg	standard conditions	Day 4	whole organism	RTPCR	Fig. 1
il6	WT	standard conditions	Prim-5	whole organism	RTPCR	Fig. 1
il6	WT	standard conditions	Day 4	whole organism	RTPCR	Fig. 1
il6	WT	standard conditions	Long-pec	whole organism	RTPCR	Fig. 1

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
WT + MO1-atg5	standard conditions	Long-pec	whole organism atg5 expression decreased amount, abnormal	Fig. 2
WT + MO1-atg5	standard conditions	Long-pec	whole organism ab2-map1lc3 labeling decreased amount, abnormal	Fig. 2
krb5Tg	standard conditions	Long-pec	whole organism il6 expression increased amount, abnormal	Fig. 1
krb5Tg	standard conditions	Long-pec	whole organism tnfa expression increased amount, abnormal	Fig. 1
krb5Tg/+	standard conditions	Long-pec	whole organism Ab6-sqstm1 labeling increased amount, abnormal	Fig. 1
krb5Tg/krb5Tg	standard conditions	Long-pec	whole organism vcp expression increased amount, abnormal	Fig. 3
krb5Tg/krb5Tg	standard conditions	Long-pec	whole organism Ab4-vcp labeling increased amount, abnormal	Fig. 4
krb5Tg/krb5Tg	standard conditions	Long-pec	whole organism Ab4-vcp labeling increased amount, abnormal	Fig. 3
krb5Tg/krb5Tg	standard conditions	Long-pec	whole organism Ab6-sqstm1 labeling increased amount, abnormal	Fig. 1
krb5Tg/krb5Tg	standard conditions	Protruding-mouth	whole organism vcp expression increased amount, abnormal	Fig. 3

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Mutations / Transgenics

Allele	Construct	Type
ck205Tg	Tg(elavl3:QFDBD-2xAD-VP16,cryaa:EGFP)	Transgenic Insertion
krb4Tg	Tg(elavl3:mCherry)	Transgenic Insertion
krb5Tg	Tg(elavl3:Hsa.TAU_P301L-2A-mCherry)	Transgenic Insertion

1 - 3 of 3

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Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
atg5	MO1-atg5	MRPHLNO
vcp	MO4-vcp	MRPHLNO

Fish

Fish
krb5Tg
krb5Tg/+
krb5Tg/krb5Tg
krb5Tg/krb5Tg + MO1-atg5
krb5Tg/krb5Tg + MO4-vcp
WT
WT + MO1-atg5
WT + MO4-vcp

Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
EGFP	EFG	EGFP
mCherry	EFG	mCherry
QF	EFG	QF

Mapping

Giong et al., 2024 ZDB-PUB-240925-2 PMID:39316141

Tau accumulation is cleared by the induced expression of VCP via autophagy

Giong et al., 2024

ZDB-PUB-240925-2
PMID:39316141