TY - JOUR
T1 - Transgenic monkey model of the polyglutamine diseases recapitulating progressive neurological symptoms
AU - Tomioka, Ikuo
AU - Ishibashi, Hidetoshi
AU - Minakawa, Eiko N.
AU - Motohashi, Hideyuki H.
AU - Takayama, Osamu
AU - Saito, Yuko
AU - Popiel, H. Akiko
AU - Puentes, Sandra
AU - Owari, Kensuke
AU - Nakatani, Terumi
AU - Nogami, Naotake
AU - Yamamoto, Kazuhiro
AU - Noguchi, Satoru
AU - Yonekawa, Takahiro
AU - Tanaka, Yoko
AU - Fujita, Naoko
AU - Suzuki, Hikaru
AU - Kikuchi, Hisae
AU - Aizawa, Shu
AU - Nagano, Seiichi
AU - Yamada, Daisuke
AU - Nishino, Ichizo
AU - Ichinohe, Noritaka
AU - Wada, Keiji
AU - Kohsaka, Shinichi
AU - Nagai, Yoshitaka
AU - Seki, Kazuhiko
N1 - Funding Information:
This work was supported in part by Intramural Research Grants for Neurological and Psychiatric Disorders from the National Center of Neurology and Psychiatry [23-9, 26-11 to K.S., Y.N., and I.T.]; a Health Labour Sciences Research Grant for Research on Development of New Drugs from the Ministry of Health, Labour and Welfare, Japan and the Japan Agency for Medical Research and Development [26-005 to K.S., Y.N., and I.T.]; Grants-in-Aid for Challenging Exploratory Research from the Japan Society for the Promotion of Science, Japan [26670446 to Y.N.]; Grants-in-Aid for Young Scientists (B) from the Japan Society for the Promotion of Science, Japan [26870884 to I.T.]; a grant from Core Research for Evolutional Science and Technology (CREST) of the Japan Science and Technology Agency to Y.N; a research grant from the ALS ?Inochi no Iro? Foundation to I.T.; and a research grant from the Takeda Science Foundation to I.T. Acknowledgments: We thank Drs. Hiroyuki Miyoshi and Atsushi Miyawaki (RIKEN) for providing lentiviral vectors and Venus constructs, Drs. Shinichi Takeda, Takashi Okada, Hironori Okada, Miho Murata, Katsuki Nakamura, Hideyuki Okano (Keio University), and Erika Sasaki (Central Institute for Experimental Animals) for their helpful discussions, and Dr. Toshihide Takeuchi, Dr. Keiko Nakagaki, Shoko Watanabe, Madoka Nakabayashi, Junichi Ueno, Ikuko Takamoto, Kouichi Nakasone, Mami Kumon, Ryoichi Saito, and Akiko Kawanobe for their technical assistance.
Funding Information:
This work was supported in part by Intramural Research Grants for Neurological and Psychiatric Disorders from the National Center of Neurology and Psychiatry [23-9, 26-11 to K.S., Y.N., and I.T.]; a Health Labour Sciences Research Grant for Research on Development of New Drugs from the Ministry of Health, Labour and Welfare, Japan and the Japan Agency for Medical Research and Development [26-005 to K.S., Y.N., and I.T.]; Grants-in-Aid for Challenging Exploratory Research from the Japan Society for the Promotion of Science, Japan [26670446 to Y.N.]; Grants-in-Aid for Young Scientists (B) from the Japan Society for the Promotion of Science, Japan [26870884 to I.T.]; a grant from Core Research for Evolutional Science and Technology (CREST) of the Japan Science and Technology Agency to Y.N; a research grant from the ALS “Inochi no Iro” Foundation to I.T.; and a research grant from the Takeda Science Foundation to I.T.
Publisher Copyright:
© 2017, Society for Neuroscience. All rights reserved.
PY - 2017
Y1 - 2017
N2 - Age-associated neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and the polyglutamine (polyQ) diseases, are becoming prevalent as a consequence of elongation of the human lifespan. Although various rodent models have been developed to study and overcome these diseases, they have limitations in their translational research utility owing to differences from humans in brain structure and function and in drug metabolism. Here, we generated a transgenic marmoset model of the polyQ diseases, showing progressive neurological symptoms including motor impairment. Seven transgenic marmosets were produced by lenti-viral introduction of the human ataxin 3 gene with 120 CAG repeats encoding an expanded polyQ stretch. Although all offspring showed no neurological symptoms at birth, three marmosets with higher transgene expression developed neurological symptoms of varying degrees at 3–4 months after birth, followed by gradual decreases in body weight gain, spontaneous activity, and grip strength, indicating time-dependent disease progression. Pathological examinations revealed neurodegeneration and intranuclear polyQ protein inclusions accompanied by gliosis, which recapitulate the neuropathological features of polyQ disease patients. Consistent with neuronal loss in the cerebellum, brain MRI analyses in one living symptomatic marmoset detected enlargement of the fourth ventricle, which suggests cerebellar atrophy. Notably, successful germline transgene transmission was confirmed in the second-generation offspring derived from the symptomatic transgenic marmoset gamete. Because the accumulation of abnormal proteins is a shared pathomechanism among various neurodegenerative diseases, we suggest that this new marmoset model will contribute toward elucidating the pathomechanisms of and developing clinically applicable therapies for neurodegenerative diseases.
AB - Age-associated neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and the polyglutamine (polyQ) diseases, are becoming prevalent as a consequence of elongation of the human lifespan. Although various rodent models have been developed to study and overcome these diseases, they have limitations in their translational research utility owing to differences from humans in brain structure and function and in drug metabolism. Here, we generated a transgenic marmoset model of the polyQ diseases, showing progressive neurological symptoms including motor impairment. Seven transgenic marmosets were produced by lenti-viral introduction of the human ataxin 3 gene with 120 CAG repeats encoding an expanded polyQ stretch. Although all offspring showed no neurological symptoms at birth, three marmosets with higher transgene expression developed neurological symptoms of varying degrees at 3–4 months after birth, followed by gradual decreases in body weight gain, spontaneous activity, and grip strength, indicating time-dependent disease progression. Pathological examinations revealed neurodegeneration and intranuclear polyQ protein inclusions accompanied by gliosis, which recapitulate the neuropathological features of polyQ disease patients. Consistent with neuronal loss in the cerebellum, brain MRI analyses in one living symptomatic marmoset detected enlargement of the fourth ventricle, which suggests cerebellar atrophy. Notably, successful germline transgene transmission was confirmed in the second-generation offspring derived from the symptomatic transgenic marmoset gamete. Because the accumulation of abnormal proteins is a shared pathomechanism among various neurodegenerative diseases, we suggest that this new marmoset model will contribute toward elucidating the pathomechanisms of and developing clinically applicable therapies for neurodegenerative diseases.
KW - Common marmoset
KW - Neurodegenerative disease
KW - Polyglutamine disease
KW - Transgenic monkey
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U2 - 10.1523/ENEURO.0250-16.2017
DO - 10.1523/ENEURO.0250-16.2017
M3 - Article
C2 - 28374014
AN - SCOPUS:85032005314
VL - 4
JO - eNeuro
JF - eNeuro
SN - 2373-2822
IS - 2
M1 - e0250-16.2017
ER -