title: Short half-lives of ataxia-associated aprataxin proteins in neuronal cells.
abstract: Early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH)/ataxia with oculomotor apraxia type 1 (AOA1) is caused by mutations in the gene encoding aprataxin (APTX). Although several in vitro findings proposed that impaired enzymatic activities of APTX are responsible for EAOH/AOA1, potential instability of mutant proteins has also been suggested as the pathogenesis based on in vivo finding that mutant proteins are almost undetectable in EAOH/AOA1 tissues or cells. The present study aimed to experimentally prove instability of mutant proteins in neuronal cells, the cell type preferentially affected by this disease. Results of pulse-chase experiments demonstrated that all of the disease-associated mutants had extremely shorter half-lives than the WT. We further found that mutants were targeted for rapid proteasome-mediated degradation. These results help establish pathogenic and physiological protein characteristics of APTX in neuronal cells.
authors.affiliation: Department of Neurology, Nara Medical University, Kashihara, Nara, Japan. hirano_makito@yahoo.co.jp
authors.forename: Makito
authors.initials: M
authors.lastname: Hirano
authors.forename: Hirohide
authors.initials: H
authors.lastname: Asai
authors.forename: Takao
authors.initials: T
authors.lastname: Kiriyama
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Furiya
authors.forename: Takaaki
authors.initials: T
authors.lastname: Iwamoto
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Nishiwaki
authors.forename: Aya
authors.initials: A
authors.lastname: Yamamoto
authors.forename: Toshio
authors.initials: T
authors.lastname: Mori
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ueno
mesh_terms: D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D004795:Enzyme Stability / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006207:Half-Life; D006801:Humans; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000378:metabolism*; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D013132:Spinocerebellar Degenerations / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D013997:Time Factors
chemical_list: C438188:APTX protein, human; D015415:Biomarkers; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D046988:Proteasome Endopeptidase Complex