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

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

doi:10.3389/fcell.2021.809942

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

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. CookYong Jie Zhang

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Article number	809942
Journal	Frontiers in Cell and Developmental Biology
Volume	9
DOIs	https://doi.org/10.3389/fcell.2021.809942
State	Published - Jan 12 2022

Keywords

C9orf72
HDAC6
amyotrophic lateral sclerosis
dipeptide repeat proteins
frontotemporal dementia

ASJC Scopus subject areas

Developmental Biology
Cell Biology

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10.3389/fcell.2021.809942

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del Rosso, G., Carlomagno, Y., Todd, T. W., Jones, C. Y., Prudencio, M., Daughrity, L. M., Yue, M., Jansen-West, K., Tong, J., Shao, W., Wu, Y., Castanedes-Casey, M., Tabassian, L., Oskarsson, B., Ling, K., Rigo, F., Dickson, D. W., Yao, T. P., Petrucelli, L., ... Zhang, Y. J. (2022). HDAC6 Interacts With Poly (GA) and Modulates its Accumulation in c9FTD/ALS. Frontiers in Cell and Developmental Biology, 9, Article 809942. https://doi.org/10.3389/fcell.2021.809942

del Rosso, G, Carlomagno, Y, Todd, TW, Jones, CY, Prudencio, M, Daughrity, LM, Yue, M, Jansen-West, K, Tong, J, Shao, W, Wu, Y, Castanedes-Casey, M, Tabassian, L, Oskarsson, B, Ling, K, Rigo, F, Dickson, DW, Yao, TP, Petrucelli, L , Cook, CN & Zhang, YJ 2022, 'HDAC6 Interacts With Poly (GA) and Modulates its Accumulation in c9FTD/ALS', Frontiers in Cell and Developmental Biology, vol. 9, 809942. https://doi.org/10.3389/fcell.2021.809942

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title = "HDAC6 Interacts With Poly (GA) and Modulates its Accumulation in c9FTD/ALS",

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 = "C9orf72, HDAC6, amyotrophic lateral sclerosis, dipeptide repeat proteins, frontotemporal dementia",

author = "{del Rosso}, Giulia and Yari Carlomagno and Todd, {Tiffany W.} and Jones, {Caroline Y.} and Mercedes Prudencio and Daughrity, {Lillian M.} and Mei Yue and Karen Jansen-West and Jimei Tong and Wei Shao and Yanwei Wu and Monica Castanedes-Casey and Lilia Tabassian and Bj{\"o}rn Oskarsson and Karen Ling and Frank Rigo and Dickson, {Dennis W.} and Yao, {Tso Pang} and Leonard Petrucelli and Cook, {Casey N.} and Zhang, {Yong Jie}",

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AU - del Rosso, Giulia

AU - Carlomagno, Yari

AU - Todd, Tiffany W.

AU - Jones, Caroline Y.

AU - Prudencio, Mercedes

AU - Daughrity, Lillian M.

AU - Yue, Mei

AU - Jansen-West, Karen

AU - Tong, Jimei

AU - Shao, Wei

AU - Wu, Yanwei

AU - Castanedes-Casey, Monica

AU - Tabassian, Lilia

AU - Oskarsson, Björn

AU - Ling, Karen

AU - Rigo, Frank

AU - Dickson, Dennis W.

AU - Yao, Tso Pang

AU - Petrucelli, Leonard

AU - Cook, Casey N.

AU - Zhang, Yong Jie

N1 - Publisher Copyright: Copyright © 2022 del Rosso, Carlomagno, Todd, Jones, Prudencio, Daughrity, Yue, Jansen-West, Tong, Shao, Wu, Castanedes-Casey, Tabassian, Oskarsson, Ling, Rigo, Dickson, Yao, Petrucelli, Cook and Zhang.

PY - 2022/1/12

Y1 - 2022/1/12

N2 - 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.

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

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