title: Transgenic mice harboring a full-length human mutant DRPLA gene exhibit age-dependent intergenerational and somatic instabilities of CAG repeats comparable with those in DRPLA patients.
abstract: Dentatorubral-pallidoluysian atrophy (DRPLA) is one among an increasing number of hereditary neurodegenerative diseases determined as being caused by unstable expansion of CAG repeats coding for polyglutamine stretches. To investigate the molecular mechanisms underlying CAG repeat instability, we established three transgenic lines each harboring a single copy of a full-length human mutant DRPLA gene carrying a CAG repeat expansion. These transgenic mice exhibited an age-dependent increase (+0.31 per year) in male transmission and an age-dependent contraction (-1.21 per year) in female transmission. Similar tendencies in intergenerational instabilities were also observed in human DRPLA parent-offspring pairs. The intergenerational instabilities of the CAG repeats may be interpreted as being derived from the instability occurring during continuous cell division of spermatogonia in the male, and that occurring during the period of meiotic arrest in the female. The transgenic mice also exhibited an age-dependent increase in the degree of somatic mosaicism which occurred in a cell lineage-dependent manner, with the size range of CAG repeats being smaller in the cerebellum than in other tissues including the cerebrum, consistent with observations in autopsied tissues of DRPLA patients. Thus, the transgenic mice described in this study exhibited age-dependent intergenerational as well as somatic instabilities of expanded CAG repeats comparable with those observed in human DRPLA patients, and are therefore expected to serve as good models for investigating the molecular mechanisms of instabilities of CAG repeats.
authors.affiliation: Department of Neurology, Brain Research Institute, Niigata University, 1 Asahimachi, Niigata 951-8585, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Sato
authors.forename: M
authors.initials: M
authors.lastname: Oyake
authors.forename: K
authors.initials: K
authors.lastname: Nakamura
authors.forename: K
authors.initials: K
authors.lastname: Nakao
authors.forename: Y
authors.initials: Y
authors.lastname: Fukusima
authors.forename: O
authors.initials: O
authors.lastname: Onodera
authors.forename: S
authors.initials: S
authors.lastname: Igarashi
authors.forename: H
authors.initials: H
authors.lastname: Takano
authors.forename: K
authors.initials: K
authors.lastname: Kikugawa
authors.forename: Y
authors.initials: Y
authors.lastname: Ishida
authors.forename: T
authors.initials: T
authors.lastname: Shimohata
authors.forename: R
authors.initials: R
authors.lastname: Koide
authors.forename: T
authors.initials: T
authors.lastname: Ikeuchi
authors.forename: H
authors.initials: H
authors.lastname: Tanaka
authors.forename: N
authors.initials: N
authors.lastname: Futamura
authors.forename: R
authors.initials: R
authors.lastname: Matsumura
authors.forename: T
authors.initials: T
authors.lastname: Takayanagi
authors.forename: F
authors.initials: F
authors.lastname: Tanaka
authors.forename: G
authors.initials: G
authors.lastname: Sobue
authors.forename: O
authors.initials: O
authors.lastname: Komure
authors.forename: M
authors.initials: M
authors.lastname: Takahashi
authors.forename: A
authors.initials: A
authors.lastname: Sano
authors.forename: Y
authors.initials: Y
authors.lastname: Ichikawa
authors.forename: J
authors.initials: J
authors.lastname: Goto
authors.forename: I
authors.initials: I
authors.lastname: Kanazawa
mesh_terms: D000328:Adult; D000375:Aging / Q000235:genetics; D000818:Animals; D001284:Atrophy; D018891:Dentate Gyrus / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005917:Globus Pallidus / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009030:Mosaicism; D009419:Nerve Tissue Proteins / Q000235:genetics*; D019636:Neurodegenerative Diseases / Q000235:genetics*; D012012:Red Nucleus / Q000473:pathology; D013045:Species Specificity; D019680:Trinucleotide Repeat Expansion
chemical_list: D009419:Nerve Tissue Proteins; C095278:atrophin-1