J Korean Med Sci.  2019 Aug;34(33):e225. 10.3346/jkms.2019.34.e225.

Targeted Downregulation of kdm4a Ameliorates Tau-engendered Defects in Drosophila melanogaster

Affiliations
  • 1Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Korea. chunys@snu.ac.kr
  • 2Department of Physiology, Seoul National University College of Medicine, Seoul, Korea.
  • 3Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.

Abstract

BACKGROUND
Tauopathies, 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 (JHDM) genes, which have yet to be studied in AD pathology.
METHODS
To examine alterations of several JHDM genes in AD pathology, we performed bioinformatics analyses of JHDM gene expression profiles in brain tissue samples from deceased AD patients. Furthermore, to investigate the possible relationship between alterations in JHDM gene expression profiles and AD pathology in vivo, we examined whether tissue-specific downregulation of JHDM Drosophila homologs (kdm) can affect tauR406W-induced neurotoxicity using transgenic flies containing the UAS-Gal4 binary system.
RESULTS
The expression levels of JHDM1A, JHDM2A/2B, and JHDM3A/3B were significantly higher in postmortem brain tissue from patients with AD than from non-demented controls, whereas JHDM1B mRNA levels were downregulated in the brains of patients with AD. Using transgenic flies, we revealed that knockdown of kdm2 (homolog to human JHDM1), kdm3 (homolog to human JHDM2), kdm4a (homolog to human JHDM3A), or kdm4b (homolog to human JHDM3B) genes in the eye ameliorated the tauR406W-engendered defects, resulting in less severe phenotypes. However, kdm4a knockdown in the central nervous system uniquely ameliorated tauR406W-induced locomotion defects by restoring heterochromatin.
CONCLUSION
Our results suggest that downregulation of kdm4a expression may be a potential therapeutic target in AD.

Keyword

Drosophila melanogaster; Tauopathy; Alzheimer's Disease; Heterochromatin; JHDM; kdm

MeSH Terms

Acetylation
Alzheimer Disease
Brain
Central Nervous System
Computational Biology
Diptera
Down-Regulation*
Drosophila melanogaster*
Drosophila*
Heterochromatin
Histones
Humans
Locomotion
Methylation
Neurodegenerative Diseases
Neurofibrillary Tangles
Pathology
Phenotype
RNA, Messenger
tau Proteins
Tauopathies
Transcriptome
Heterochromatin
Histones
RNA, Messenger
tau Proteins
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