HDAC6 Interacts With Poly (GA) and Modulates Its Accumulation in C9FTD/ALS

Overview

Journal Front Cell Dev Biol

Specialty Cell Biology

Date 2022 Jan 31

PMID 35096836

Authors

Giulia Del Rosso

Yari Carlomagno

Tiffany W Todd

Caroline Y Jones

Mercedes Prudencio

Lillian M Daughrity

Mei Yue

Karen Jansen-West

Jimei Tong

Wei Shao

Yanwei Wu

Monica Castanedes-Casey

Lilia Tabassian

Bjorn Oskarsson

Karen Ling

Frank Rigo

Dennis W Dickson

Tso-Pang Yao

Leonard Petrucelli

Casey N Cook

Yong Jie Zhang

Affiliations

Soon will be listed here.

Abstract

The aberrant translation of a repeat expansion in chromosome 9 open reading frame 72 (), the most common cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), results in the accumulation of toxic dipeptide repeat (DPR) proteins in the central nervous system We have found that, among the sense DPR proteins, HDAC6 specifically interacts with the poly (GA) and co-localizes with inclusions in both patient tissue and a mouse model of this disease (c9FTD/ALS). Overexpression of HDAC6 increased poly (GA) levels in cultured cells independently of HDAC6 deacetylase activity, suggesting that HDAC6 can modulate poly (GA) pathology through a mechanism that depends upon their physical interaction. Moreover, decreasing HDAC6 expression by stereotaxic injection of antisense oligonucleotides significantly reduced the number of poly (GA) inclusions in c9FTD/ALS mice. These findings suggest that pharmacologically reducing HDAC6 levels could be of therapeutic value in c9FTD/ALS.

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