title: Transgenic Monkey Model of the Polyglutamine Diseases Recapitulating Progressive Neurological Symptoms.
abstract: 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.
authors.affiliation: Department of Neurophysiology, National Institute of Neuroscience National Center of Neurology and Psychiatry , Tokyo 187-8502, Japan.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Tomioka
authors.affiliation: Department of Neurophysiology, National Institute of Neuroscience National Center of Neurology and Psychiatry , Tokyo 187-8502, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Ishibashi
authors.affiliation: Department of Degenerative Neurological Diseases, National Institute of Neuroscience National Center of Neurology and Psychiatry , Tokyo 187-8502, Japan.
authors.forename: Eiko N
authors.initials: EN
authors.lastname: Minakawa
authors.affiliation: Department of Neurophysiology, National Institute of Neuroscience National Center of Neurology and Psychiatry , Tokyo 187-8502, Japan.
authors.forename: Hideyuki H
authors.initials: HH
authors.lastname: Motohashi
authors.affiliation: Department of Neurophysiology, National Institute of Neuroscience National Center of Neurology and Psychiatry , Tokyo 187-8502, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Takayama
authors.affiliation: Department of Pathology and Laboratory Medicine, National Institute of Neuroscience National Center of Neurology and Psychiatry , Tokyo 187-8502, Japan.
authors.forename: Yuko
authors.identifier: 0000-0002-1808-3647
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Department of Degenerative Neurological Diseases, National Institute of Neuroscience National Center of Neurology and Psychiatry , Tokyo 187-8502, Japan.
authors.forename: H Akiko
authors.initials: HA
authors.lastname: Popiel
authors.affiliation: Department of Neurophysiology, National Institute of Neuroscience National Center of Neurology and Psychiatry , Tokyo 187-8502, Japan.
authors.forename: Sandra
authors.initials: S
authors.lastname: Puentes
authors.affiliation: Department of Neurophysiology, National Institute of Neuroscience National Center of Neurology and Psychiatry , Tokyo 187-8502, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Owari
authors.affiliation: Department of Neurophysiology, National Institute of Neuroscience National Center of Neurology and Psychiatry , Tokyo 187-8502, Japan.
authors.forename: Terumi
authors.initials: T
authors.lastname: Nakatani
authors.affiliation: Department of Neurophysiology, National Institute of Neuroscience National Center of Neurology and Psychiatry , Tokyo 187-8502, Japan.
authors.forename: Naotake
authors.initials: N
authors.lastname: Nogami
authors.affiliation: Division of Laboratory Animals Resources, National Institute of Neuroscience National Center of Neurology and Psychiatry , Tokyo 187-8502, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Department of Neuromuscular Research, National Institute of Neuroscience National Center of Neurology and Psychiatry , Tokyo 187-8502, Japan.
authors.forename: Satoru
authors.identifier: 0000-0001-6165-3716
authors.initials: S
authors.lastname: Noguchi
authors.affiliation: Department of Neuromuscular Research, National Institute of Neuroscience National Center of Neurology and Psychiatry , Tokyo 187-8502, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yonekawa
authors.affiliation: Department of Pathology and Laboratory Medicine, National Institute of Neuroscience National Center of Neurology and Psychiatry , Tokyo 187-8502, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Department of Neurophysiology, National Institute of Neuroscience National Center of Neurology and Psychiatry , Tokyo 187-8502, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Fujita
authors.affiliation: Department of Neurophysiology, National Institute of Neuroscience National Center of Neurology and Psychiatry , Tokyo 187-8502, Japan.
authors.forename: Hikaru
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Department of Degenerative Neurological Diseases, National Institute of Neuroscience National Center of Neurology and Psychiatry , Tokyo 187-8502, Japan.
authors.forename: Hisae
authors.identifier: 0000-0003-3813-9879
authors.initials: H
authors.lastname: Kikuchi
authors.affiliation: Department of Degenerative Neurological Diseases, National Institute of Neuroscience National Center of Neurology and Psychiatry , Tokyo 187-8502, Japan.
authors.forename: Shu
authors.initials: S
authors.lastname: Aizawa
authors.affiliation: Department of Peripheral Nervous System Research, National Institute of Neuroscience National Center of Neurology and Psychiatry , Tokyo 187-8502, Japan.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Nagano
authors.affiliation: Department of Degenerative Neurological Diseases, National Institute of Neuroscience National Center of Neurology and Psychiatry , Tokyo 187-8502, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yamada
authors.affiliation: Department of Neuromuscular Research, National Institute of Neuroscience National Center of Neurology and Psychiatry , Tokyo 187-8502, Japan.
authors.forename: Ichizo
authors.identifier: 0000-0001-9452-112X
authors.initials: I
authors.lastname: Nishino
authors.affiliation: Department of Ultrastructural Research, National Institute of Neuroscience National Center of Neurology and Psychiatry , Tokyo 187-8502, Japan.
authors.forename: Noritaka
authors.identifier: 0000-0002-8323-4552
authors.initials: N
authors.lastname: Ichinohe
authors.affiliation: Department of Degenerative Neurological Diseases, National Institute of Neuroscience National Center of Neurology and Psychiatry , Tokyo 187-8502, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Wada
authors.affiliation: Department of Neurochemistry, National Institute of Neuroscience National Center of Neurology and Psychiatry , Tokyo 187-8502, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kohsaka
authors.affiliation: Department of Degenerative Neurological Diseases, National Institute of Neuroscience National Center of Neurology and Psychiatry , Tokyo 187-8502, Japan.
authors.forename: Yoshitaka
authors.identifier: 0000-0003-1037-3129
authors.initials: Y
authors.lastname: Nagai
authors.affiliation: Department of Neurophysiology, National Institute of Neuroscience National Center of Neurology and Psychiatry , Tokyo 187-8502, Japan.
authors.forename: Kazuhiko
authors.identifier: 0000-0002-4262-9590
authors.initials: K
authors.lastname: Seki
mesh_terms: D000375:Aging / Q000473:pathology / Q000502:physiology; D000818:Animals; D030801:Animals, Genetically Modified; D000067699:Ataxin-3 / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D002144:Callithrix; D002460:Cell Line; D004195:Disease Models, Animal; D018450:Disease Progression; D004423:Ear; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005822:Genetic Vectors; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008297:Male; D009043:Motor Activity / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000378:metabolism; D010641:Phenotype; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D019680:Trinucleotide Repeat Expansion
chemical_list: D010455:Peptides; D012097:Repressor Proteins; C097188:polyglutamine; C092341:ATXN3 protein, human; D000067699:Ataxin-3
keywords: Common marmoset; Neurodegenerative disease; Polyglutamine disease; Transgenic monkey