title: Tissue transglutaminase crosslinks ataxin-1: possible role in SCA1 pathogenesis.
abstract: Transglutaminase type 2 (TG2) has recently been implicated in crosslinking of mutant huntingtin protein into aggregates. Here we show that TG2 also crosslinks spinocerebellar ataxia-1 (SCA1) gene product ataxin-1. HeLa cell lysates expressing GFP tagged ataxin-1 with 2, 30 or 82 glutamines showed covalent crosslinking of ataxin-1 when incubated with exogenously added TG2. This crosslinking was inhibited by TG2 inhibitor cystamine. SCA1 transgenic mice which overexpress the mutant ataxin-1 in cerebellar Purkinje cells showed elevated nuclear TG2 in the absence of ataxin-1 nuclear aggregates. The addition of purified TG2 to the nuclear extracts or addition of SCA1 nuclear TG2 to GFP-Q82 HeLa cell lysates resulted in the formation of insoluble aggregates. These data indicate that ataxin-1 is a substrate of TG2. Further, in SCA1 TG2 may translocate to the nucleus in response to nuclear accumulation of mutant ataxin-1 at early stages of the disease.
authors.affiliation: Department of Neurology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: D'Souza
authors.forename: J
authors.initials: J
authors.lastname: Wei
authors.forename: Q
authors.initials: Q
authors.lastname: Shao
authors.forename: M D
authors.initials: MD
authors.lastname: Hebert
authors.forename: S H
authors.initials: SH
authors.lastname: Subramony
authors.forename: P J S
authors.initials: PJ
authors.lastname: Vig
mesh_terms: D000818:Animals; D000067696:Ataxin-1; D000067528:Ataxins; D064026:Calbindins; D002531:Cerebellum / Q000473:pathology; D003543:Cysteamine / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000235:genetics*; D008040:Genetic Linkage; D006367:HeLa Cells; D006579:Heterozygote; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D020754:Spinocerebellar Ataxias / Q000235:genetics* / Q000473:pathology; D011503:Transglutaminases / Q000235:genetics*
chemical_list: C000593749:ATXN1 protein, human; D000067696:Ataxin-1; D000067528:Ataxins; C000593750:Atxn1 protein, mouse; D064026:Calbindins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D064030:S100 Calcium Binding Protein G; D003543:Cysteamine; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins