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.
Footnotes
The authors declare no competing financial interests.
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.
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.