title: C-terminal deletion of the atrophin-1 protein results in growth retardation but not neurodegeneration in mice.
abstract: Dentatorubral-pallidoluysian atrophy (DRPLA) is a dominant hereditary neurodegenerative disorder caused by the expansion of a poly-glutamine (poly-Q) repeat in Atrophin-1 protein. Ectopic expression of a poly-Q expanded human Atrophin-1 is sufficient to induce DRPLA phenotypes in mice. However, it is still unclear whether the dominant effect of poly-Q expansion is due to the functional interference with wild-type Atrophin-1 proteins, which exist in both patients and transgenic mice. Here we report the generation and analysis of an Atrophin-1 targeting allele that expresses a truncated protein lacking both the poly-Q repeat and following C-terminal peptides. Homozygous mutants exhibit growth retardation and progressive male infertility, but no obvious signs of neurodegeneration. Moreover, the mutant allele neither blocked nor enhanced the neurodegenerative phenotypes caused by a poly-Q expanded transgene. These results support the model that poly-Q expanded Atrophin-1 proteins cause DRPLA in a manner independent of any functional interaction with wild-type Atrophin-1 proteins.
authors.affiliation: Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Juehua
authors.initials: J
authors.lastname: Yu
authors.forename: Mingyao
authors.initials: M
authors.lastname: Ying
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhuang
authors.forename: Tian
authors.initials: T
authors.lastname: Xu
authors.forename: Min
authors.initials: M
authors.lastname: Han
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Wu
authors.forename: Rener
authors.initials: R
authors.lastname: Xu
mesh_terms: D000818:Animals; D001835:Body Weight; D001921:Brain / Q000166:cytology / Q000378:metabolism; D042622:DNA Repeat Expansion; D004435:Eating; D005298:Fertility / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007328:Insulin / Q000097:blood; D020738:Leptin / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020191:Myoclonic Epilepsies, Progressive / Q000235:genetics; D009410:Nerve Degeneration / Q000235:genetics* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000235:genetics; D010641:Phenotype; D045442:Rotarod Performance Test; D017384:Sequence Deletion; D015996:Survival Rate; D013737:Testis / Q000166:cytology / Q000378:metabolism
chemical_list: D007328:Insulin; D020738:Leptin; D009419:Nerve Tissue Proteins; D010455:Peptides; C095278:atrophin-1; C097188:polyglutamine