Frontiers in Cell and Developmental Biology (Jan 2022)
HDAC6 Interacts With Poly (GA) and Modulates its Accumulation in c9FTD/ALS
- Giulia del Rosso,
- Giulia del Rosso,
- Yari Carlomagno,
- Tiffany W. Todd,
- Caroline Y. Jones,
- Mercedes Prudencio,
- 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,
- Dennis W. Dickson,
- Tso-Pang Yao,
- Leonard Petrucelli,
- Leonard Petrucelli,
- Casey N. Cook,
- Casey N. Cook,
- Yong Jie Zhang,
- Yong Jie Zhang
Affiliations
- Giulia del Rosso
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
- Giulia del Rosso
- Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL, United States
- Yari Carlomagno
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
- Tiffany W. Todd
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
- Caroline Y. Jones
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
- Mercedes Prudencio
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
- Mercedes Prudencio
- Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL, United States
- Lillian M. Daughrity
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
- Mei Yue
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
- Karen Jansen-West
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
- Jimei Tong
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
- Wei Shao
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
- Yanwei Wu
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
- Monica Castanedes-Casey
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
- Lilia Tabassian
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
- Björn Oskarsson
- Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
- Karen Ling
- Ionis Pharmaceuticals, Carlsbad, CA, United States
- Frank Rigo
- Ionis Pharmaceuticals, Carlsbad, CA, United States
- Dennis W. Dickson
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
- Dennis W. Dickson
- Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL, United States
- Tso-Pang Yao
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, United States
- Leonard Petrucelli
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
- Leonard Petrucelli
- Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL, United States
- Casey N. Cook
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
- Casey N. Cook
- Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL, United States
- Yong Jie Zhang
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
- Yong Jie Zhang
- Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL, United States
- DOI
- https://doi.org/10.3389/fcell.2021.809942
- Journal volume & issue
-
Vol. 9
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.
Keywords
