RT Journal Article
SR Electronic
T1 Transgenic Monkey Model of the Polyglutamine Diseases Recapitulating Progressive Neurological Symptoms
JF eneuro
JO eNeuro
FD Society for Neuroscience
SP ENEURO.0250-16.2017
DO 10.1523/ENEURO.0250-16.2017
VO 4
IS 2
A1 Tomioka, Ikuo
A1 Ishibashi, Hidetoshi
A1 Minakawa, Eiko N.
A1 Motohashi, Hideyuki H.
A1 Takayama, Osamu
A1 Saito, Yuko
A1 Popiel, H. Akiko
A1 Puentes, Sandra
A1 Owari, Kensuke
A1 Nakatani, Terumi
A1 Nogami, Naotake
A1 Yamamoto, Kazuhiro
A1 Noguchi, Satoru
A1 Yonekawa, Takahiro
A1 Tanaka, Yoko
A1 Fujita, Naoko
A1 Suzuki, Hikaru
A1 Kikuchi, Hisae
A1 Aizawa, Shu
A1 Nagano, Seiichi
A1 Yamada, Daisuke
A1 Nishino, Ichizo
A1 Ichinohe, Noritaka
A1 Wada, Keiji
A1 Kohsaka, Shinichi
A1 Nagai, Yoshitaka
A1 Seki, Kazuhiko
YR 2017
UL http://www.eneuro.org/content/4/2/ENEURO.0250-16.2017.abstract
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 lentiviral 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.