Targeted downregulation of Hipp1 ameliorates tau-engendered deficits in Drosophila melanogaster
Authors: SUNG YEON PARK 1,3; JIEUN SEO 2; Seulbee Lee 2; Sang Jeong Kim 1,2,3; Yang-Sook Chun 1,2,3
Affiliations: 1) Ischemic/Hypoxic Disease Institute, Seoul National University, College of Medicine, Seoul, Republic of Korea; 2) Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea; 3) Department of Physiology, Seoul National University College of Medicine, Seoul, Republic of Korea
Keywords: a. neural degeneration; f. insulators/boundary elements
Tauopathies, such as Alzheimer’s disease (AD), are neurodegenerative diseases characterized by the deposition of neurofibrillary tangles comprising hyperphosphorylated tau protein in the human brain. Given that abnormal epigenetic alterations in heterochromatin configuration have been documented in AD patients and transgenic animal models of AD, we investigated the roles of novel heterochromatin-associated interactors in tauopathies. We examined whether tissue-specific downregulation or loss-of-function alleles of heterochromatin-associated interactors can affect tau-induced neurotoxicity using transgenic flies via UAS-Gal4 binary system. Here, we found that knockdown of HP1 and insulator partner protein (Hipp1) ameliorates tau-engendered eye defects, locomotion defects, reduced lifespan, weight loss, and neurodegeneration by preventing hyperphosphorylation of tau. Nonetheless, RNAi-mediated reduction of Hipp1 failed to restore tau-induced heterochromatin loosening; it accelerated abnormal overexpression of heterochromatic genes. Instead, knockdown of Hipp1 restored tau-driven aberrant expression of putative insulator targets and aberrant insulator-mediated epigenetic alterations. HIPP1 may have a role as an insulator binding partner regarding to be implicated in tau-induced neurodegeneration. Moreover, knockdown of Hipp1 in flies overexpressing tau restored the aberrant expression of AD susceptibility genes, Amph and Sox102F. These results suggest that downregulation of Hipp1 expression may be a potential therapeutic target in neurodegenerative diseases; they also provide new insights regarding the roles of insulator proteins in tauopathies.