Antisense oligonucleotide therapy rescues aggresome formation in a novel spinocerebellar ataxia type 3 human embryonic stem cell line

Spinocerebellar ataxia type 3 (SCA3) is a fatal, late-onset neurodegenerative disorder characterized by selective neuropathology in the brainstem, cerebellum, spinal cord, and substantia nigra. Here we report the first NIH-approved human embryonic stem cell (hESC) line derived from an embryo harbori...

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Main Authors:	Lauren R. Moore, Laura Keller, David D. Bushart, Rodrigo G. Delatorre, Duojia Li, Hayley S. McLoughlin, Maria do Carmo Costa, Vikram G. Shakkottai, Gary D. Smith, Henry L. Paulson
Format:	Article
Language:	English
Published:	Elsevier 2019-08-01
Series:	Stem Cell Research
Online Access:	http://www.sciencedirect.com/science/article/pii/S1873506119301345

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spelling	doaj-baa1709cd0724ff39534f48c27b23c732020-11-25T00:40:03ZengElsevierStem Cell Research1873-50612019-08-0139Antisense oligonucleotide therapy rescues aggresome formation in a novel spinocerebellar ataxia type 3 human embryonic stem cell lineLauren R. Moore0Laura Keller1David D. Bushart2Rodrigo G. Delatorre3Duojia Li4Hayley S. McLoughlin5Maria do Carmo Costa6Vikram G. Shakkottai7Gary D. Smith8Henry L. Paulson9Department of Neurology, 109 Zina Pitcher Place, University of Michigan, Ann Arbor, MI 48109, United States; Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI 48109, United StatesMStem Cell Laboratories, University of Michigan, Ann Arbor, MI 48109, United StatesDepartment of Neurology, 109 Zina Pitcher Place, University of Michigan, Ann Arbor, MI 48109, United StatesDepartment of Neurology, 109 Zina Pitcher Place, University of Michigan, Ann Arbor, MI 48109, United StatesDepartment of Neurology, 109 Zina Pitcher Place, University of Michigan, Ann Arbor, MI 48109, United StatesDepartment of Neurology, 109 Zina Pitcher Place, University of Michigan, Ann Arbor, MI 48109, United StatesDepartment of Neurology, 109 Zina Pitcher Place, University of Michigan, Ann Arbor, MI 48109, United StatesDepartment of Neurology, 109 Zina Pitcher Place, University of Michigan, Ann Arbor, MI 48109, United StatesMStem Cell Laboratories, University of Michigan, Ann Arbor, MI 48109, United States; Departments of Ob/Gyn, Physiology, Urology, University of Michigan, Ann Arbor, MI 48109, United StatesDepartment of Neurology, 109 Zina Pitcher Place, University of Michigan, Ann Arbor, MI 48109, United States; Corresponding author at: Department of Neurology, University of Michigan, A. Alfred Taubman Biomedical Sciences Research Building, Room 4001, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, United States.Spinocerebellar ataxia type 3 (SCA3) is a fatal, late-onset neurodegenerative disorder characterized by selective neuropathology in the brainstem, cerebellum, spinal cord, and substantia nigra. Here we report the first NIH-approved human embryonic stem cell (hESC) line derived from an embryo harboring the SCA3 mutation. Referred to as SCA3-hESC, this line is heterozygous for the mutant polyglutamine-encoding CAG repeat expansion in the ATXN3 gene. We observed relevant molecular hallmarks of the human disease at all differentiation stages from stem cells to cortical neurons, including robust ATXN3 aggregation and altered expression of key components of the protein quality control machinery. In addition, SCA3-hESCs exhibit nuclear accumulation of mutant ATXN3 and form p62-positive aggresomes. Finally, antisense oligonucleotide-mediated reduction of ATXN3 markedly suppressed aggresome formation. The SCA3-hESC line offers a unique and highly relevant human disease model that holds strong potential to advance understanding of SCA3 disease mechanisms and facilitate the evaluation of candidate therapies for SCA3. Keywords: Aggresome, Antisense oligonucleotide, Ataxin-3, Machado-Joseph disease, Neurodegeneration, Polyglutamine diseasehttp://www.sciencedirect.com/science/article/pii/S1873506119301345
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Lauren R. Moore Laura Keller David D. Bushart Rodrigo G. Delatorre Duojia Li Hayley S. McLoughlin Maria do Carmo Costa Vikram G. Shakkottai Gary D. Smith Henry L. Paulson
spellingShingle	Lauren R. Moore Laura Keller David D. Bushart Rodrigo G. Delatorre Duojia Li Hayley S. McLoughlin Maria do Carmo Costa Vikram G. Shakkottai Gary D. Smith Henry L. Paulson Antisense oligonucleotide therapy rescues aggresome formation in a novel spinocerebellar ataxia type 3 human embryonic stem cell line Stem Cell Research
author_facet	Lauren R. Moore Laura Keller David D. Bushart Rodrigo G. Delatorre Duojia Li Hayley S. McLoughlin Maria do Carmo Costa Vikram G. Shakkottai Gary D. Smith Henry L. Paulson
author_sort	Lauren R. Moore
title	Antisense oligonucleotide therapy rescues aggresome formation in a novel spinocerebellar ataxia type 3 human embryonic stem cell line
title_short	Antisense oligonucleotide therapy rescues aggresome formation in a novel spinocerebellar ataxia type 3 human embryonic stem cell line
title_full	Antisense oligonucleotide therapy rescues aggresome formation in a novel spinocerebellar ataxia type 3 human embryonic stem cell line
title_fullStr	Antisense oligonucleotide therapy rescues aggresome formation in a novel spinocerebellar ataxia type 3 human embryonic stem cell line
title_full_unstemmed	Antisense oligonucleotide therapy rescues aggresome formation in a novel spinocerebellar ataxia type 3 human embryonic stem cell line
title_sort	antisense oligonucleotide therapy rescues aggresome formation in a novel spinocerebellar ataxia type 3 human embryonic stem cell line
publisher	Elsevier
series	Stem Cell Research
issn	1873-5061
publishDate	2019-08-01
description	Spinocerebellar ataxia type 3 (SCA3) is a fatal, late-onset neurodegenerative disorder characterized by selective neuropathology in the brainstem, cerebellum, spinal cord, and substantia nigra. Here we report the first NIH-approved human embryonic stem cell (hESC) line derived from an embryo harboring the SCA3 mutation. Referred to as SCA3-hESC, this line is heterozygous for the mutant polyglutamine-encoding CAG repeat expansion in the ATXN3 gene. We observed relevant molecular hallmarks of the human disease at all differentiation stages from stem cells to cortical neurons, including robust ATXN3 aggregation and altered expression of key components of the protein quality control machinery. In addition, SCA3-hESCs exhibit nuclear accumulation of mutant ATXN3 and form p62-positive aggresomes. Finally, antisense oligonucleotide-mediated reduction of ATXN3 markedly suppressed aggresome formation. The SCA3-hESC line offers a unique and highly relevant human disease model that holds strong potential to advance understanding of SCA3 disease mechanisms and facilitate the evaluation of candidate therapies for SCA3. Keywords: Aggresome, Antisense oligonucleotide, Ataxin-3, Machado-Joseph disease, Neurodegeneration, Polyglutamine disease
url	http://www.sciencedirect.com/science/article/pii/S1873506119301345
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Antisense oligonucleotide therapy rescues aggresome formation in a novel spinocerebellar ataxia type 3 human embryonic stem cell line

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