DataSheet1_HDAC6 Interacts With Poly (GA) and Modulates its Accumulation in c9FTD/ALS.doc (109.5 kB)
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DataSheet1_HDAC6 Interacts With Poly (GA) and Modulates its Accumulation in c9FTD/ALS.doc

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posted on 12.01.2022, 05:09 authored by 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, Björn Oskarsson, Karen Ling, Frank Rigo, Dennis W. Dickson, Tso-Pang Yao, Leonard Petrucelli, Casey N. Cook, Yong Jie Zhang

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.

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