TY - JOUR
T1 - Antisense oligonucleotide therapy rescues aggresome formation in a novel spinocerebellar ataxia type 3 human embryonic stem cell line
AU - Moore, Lauren R.
AU - Keller, L.
AU - Bushart, David D.
AU - Delatorre, Rodrigo G.
AU - Li, Duojia
AU - McLoughlin, Hayley S.
AU - do Carmo Costa, M.
AU - Shakkottai, Vikram G.
AU - Smith, Gary D.
AU - Paulson, Henry L.
N1 - Funding Information:
This work was supported in part by a Michigan Brain Initiative Predoctoral Fellowship for Neuroscience (to L.R.M.), the University of Michigan Neuroscience Graduate Program (to L.R.M.), the SCA3 Ataxia Research Fund provided in part by the SCA Network, NIH grant funding (R01-NS038712 to PI H.L.P.) and MStem Cell Funding by the University of Michigan Presidents' Office, Michigan Medicine Dean's Office, A. Alfred Taubman Medical Institute and Department of Ob/Gyn. We thank Ionis Pharmaceuticals for generating and providing the anti-ATXN3 ASO. L.R.M. G.D.S. and H.L.P. conceived and designed the study. L.K. and G.D.S. generated the SCA3-hESC line from the donated human embryo. L.R.M. L.K. D.D.B. R.D. D.L. M.C.C. and H.S.M. performed the experiments. L.R.M. analyzed the data. V.G.S. G.D.S. and H.L.P. provided supervision for experimentation and data analysis. L.R.M. wrote the manuscript with immense support provided through discussions with and supervision by G.D.S. and H.L.P. All authors read and approved of manuscript.
Funding Information:
This work was supported in part by a Michigan Brain Initiative Predoctoral Fellowship for Neuroscience (to L.R.M.), the University of Michigan Neuroscience Graduate Program (to L.R.M.), the SCA3 Ataxia Research Fund provided in part by the SCA Network , NIH grant funding ( R01-NS038712 to PI H.L.P.) and MStem Cell Funding by the University of Michigan Presidents' Office , Michigan Medicine Dean's Office , A. Alfred Taubman Medical Institute and Department of Ob/Gyn .
Publisher Copyright:
© 2019
PY - 2019/8
Y1 - 2019/8
N2 - 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.
AB - 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.
KW - Aggresome
KW - Antisense oligonucleotide
KW - Ataxin-3
KW - Machado-Joseph disease
KW - Neurodegeneration
KW - Polyglutamine disease
UR - http://www.scopus.com/inward/record.url?scp=85069880001&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85069880001&partnerID=8YFLogxK
U2 - 10.1016/j.scr.2019.101504
DO - 10.1016/j.scr.2019.101504
M3 - Article
C2 - 31374463
AN - SCOPUS:85069880001
SN - 1873-5061
VL - 39
JO - Stem Cell Research
JF - Stem Cell Research
M1 - 101504
ER -