HDAC6 Interacts With Poly (GA) and Modulates its Accumulation in c9FTD/ALS.

Giulia Del Rosso,Karen Jansen-West,Tiffany W Todd,Leonard Petrucelli,Yong Jie Zhang,Dennis W Dickson,Caroline Y Jones,Mei Yue,Wei Shao,Mercedes Prudencio,Frank Rigo,Björn Oskarsson,Jimei Tong,Lillian M Daughrity,Yanwei Wu,Karen Ling,Yari Carlomagno,Lilia J Tabassian ,Tso‐Pang Yao ,Casey Cook ,Monica Castanedes‐Casey

doi:10.3389/fcell.2021.809942

Abstract

The aberrant translation of a repeat expansion in chromosome 9 open reading frame 72 (C9orf72), 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.

Highlights

Frontotemporal dementia (FTD), caused by frontotemporal lobar degeneration (FTLD) in the brain, can be characterized by a range of clinical symptoms, including dementia, language impairment, and changes in personality and behavior
Given that histone deacetylase 6 (HDAC6) co-aggregates with ubiquitin and α-synuclein in Parkinson’s disease (Kawaguchi et al, 2003), and elevated HDAC6 expression has been reported in FTLD patients with TAR DNA-binding protein 43 (TDP-43) pathology (Odagiri et al, 2013), we wanted to examine the pattern of HDAC6 immunoreactivity in affected regions of the brain in both sporadic and c9FTD/amyotrophic lateral sclerosis (ALS) patients
Since the presence of dipeptide repeat (DPR) protein pathology differentiates c9FTD/ALS from sFTD/ALS, we examined whether the HDAC6-positive inclusions co-localized with the most abundant DPR proteins, namely poly (GA), poly (GP), and poly (GR)

Summary

Introduction

Frontotemporal dementia (FTD), caused by frontotemporal lobar degeneration (FTLD) in the brain, can be characterized by a range of clinical symptoms, including dementia, language impairment, and changes in personality and behavior. Amyotrophic lateral sclerosis (ALS) is caused by the degeneration ofi motor neurons and is characterized by a progressive loss of motor control. FTD and ALS share several genetic and pathologic features and are considered part of the same disease spectrum. As the most common genetic cause of both FTD and ALS, cases with G4C2 hexanucleotide repeat expansions in the C9orf gene are collectively referred to as c9FTD/ALS. In addition to the aggregation of TAR DNA-binding protein 43 (TDP-43), protein inclusions. Frontiers in Cell and Developmental Biology | www.frontiersin.org del Rosso et al

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