Targeted Downregulation ofkdm4aAmeliorates Tau-engendered Defects inDrosophila melanogaster

Aug 23, 2019Journal of Korean medical science

Reducing kdm4a improves tau-related problems in fruit flies

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Abstract

The expression levels of several Jumonji domain-containing histone demethylase genes were significantly higher in postmortem brain tissue from Alzheimer's disease patients compared to non-demented controls.

Higher expression levels of JHDM1A, JHDM2A/2B, and JHDM3A/3B were observed in Alzheimer's disease brain tissue.
mRNA levels of kdm4a were downregulated in the brains of Alzheimer's patients.
Knockdown of kdm2, kdm3, or kdm4a in transgenic flies improved tau-induced defects, indicating a potential protective effect.
Specifically, kdm4a knockdown in the central nervous system restored heterochromatin and ameliorated locomotion defects caused by tau.

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BACKGROUND: , a class of neurodegenerative diseases that includes Alzheimer's disease (AD), are characterized by the deposition of neurofibrillary tangles composed of hyperphosphorylated tau protein in the human brain. As abnormal alterations in histone acetylation and methylation show a cause and effect relationship with AD, we investigated the role of several Jumonji domain-containing histone demethylase () genes, which have yet to be studied in AD pathology. JHDM

METHODS: To examine alterations of severalgenes in AD pathology, we performed bioinformatics analyses ofgene expression profiles in brain tissue samples from deceased AD patients. Furthermore, to investigate the possible relationship between alterations ingene expression profiles and AD pathology in vivo, we examined whether tissue-specific downregulation ofhomologs () can affect tau-induced neurotoxicity using transgenic flies containing the UAS-Gal4 binary system. JHDM JHDM JHDM JHDM Drosophila kdm R406W

RESULTS: The expression levels of,, andwere significantly higher in postmortem brain tissue from patients with AD than from non-demented controls, whereasmRNA levels were downregulated in the brains of patients with AD. Using transgenic flies, we revealed that knockdown of(homolog to human),(homolog to human),(homolog to human), or(homolog to human) genes in the eye ameliorated the tau-engendered defects, resulting in less severe phenotypes. However, kdm4a knockdown in the central nervous system uniquely ameliorated tau-induced locomotion defects by restoring heterochromatin. JHDM1A JHDM2A/2B JHDM3A/3B JHDM1B kdm2JHDM1kdm3JHDM2kdm4a JHDM3A kdm4b JHDM3B R406W R406W

CONCLUSION: Our results suggest that downregulation ofexpression may be a potential therapeutic target in AD. kdm4a

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Increased expression of histone demethylases

Patients with AD vs. non-demented controls in postmortem brain tissue.

80%

Climbing ability improvement

Climbing ability of flies with kdm4a knockdown vs. 50% in tau-overexpressing flies.

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Targeted Downregulation ofkdm4aAmeliorates Tau-engendered Defects inDrosophila melanogaster

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