splice isoforms of the polyglutamine disease protein ataxin-3 exhibit similar enzymatic yet different aggregation properties受到多麸醯胺酸拼接亚型的疾病蛋白质ataxin-3展览的酶不同聚合属性.pdf

Splice Isoforms of the Polyglutamine Disease Protein Ataxin-3 Exhibit Similar Enzymatic yet Different Aggregation Properties 1 2¤ 3 4 3 Ginny Marie Harris , Katerina Dodelzon , Lijie Gong , Pedro Gonzalez-Alegre , Henry L. Paulson * 1 Graduate Program in Molecular and Cellular Biology and Medical Scientist Training Program, University of Iowa, Iowa City, Iowa, United States of America, 2 University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America, 3 Department of Neurology, University of Michigan, Ann Arbor, Michigan, United States of America, 4 Department of Neurology, University of Iowa, Iowa City, Iowa, United States of America Abstract Protein context clearly influences neurotoxicity in polyglutamine diseases, but the contribution of alternative splicing to this phenomenon has rarely been investigated. Ataxin-3, a deubiquitinating enzyme and the disease protein in SCA3, is alternatively spliced to encode either a C-terminal hydrophobic stretch or a third ubiquitin interacting motif (termed 2UIM and 3UIM isoforms, respectively). In light of emerging insights into ataxin-3 function, we examined the significance of this splice variation. We confirmed neural expression of several minor 59 variants and both of the known 39 ataxin-3 splice variants. Regardless of polyglutamine expansion, 3UIM ataxin-3 is the predominant isoform in brain. Although 2UIM and 3UIM ataxin-3 display similar in vitro deubiquitinating activity, 2UIM ataxin-3 is more prone to aggregate and more rapidly degraded by the proteasome. Our data demonstrate how alternative splicing of sequences distinct from the trinucleotide repeat can alter properties of the encoded polyglutamine disea