Ataxin-7 interacts with a Cbl-associated protein that it recruits into neuronal intranuclear inclusions

Spinocerebellar ataxia 7 (SCA7) is a neurodegenerative disease caused by ex pansion of a CAG repeat in the coding region of the SCA7 gene. The disease primarily affects the cerebellum and the retina, but also many other centra l nervous system (CNS) structures as the disease progresses. Ataxin-7, enco ded by the SCA7 gene, is a protein of unknown function expressed in many ti ssues including the CNS, In normal brain, ataxin-7 is found in the cytoplas m and/or nucleus of neurons, but in SCA7 brain ataxin-7 accumulates in intr anuclear inclusions. Ataxin-7 is expressed ubiquitously, but mutation leads to neuronal death in only certain areas of the brain. This selective patte rn of degeneration might be explained by interaction with a partner that is specifically expressed in vulnerable cells. We used a two-hybrid approach to screen a human retina cDNA library for ataxin-7-binding proteins, and is olated R85, a splice variant of Cbl-associated protein (CAP), R85 and CAP a re generated by alternative splicing of the gene SH3P12 which we localized on chromosome 10q23-q24, The interaction between ataxin-7 and the SH3P12 ge ne products (SH3P12GPs) was confirmed by pull-down and coimmunoprecipitatio n. SH3P12GPs are expressed in Purkinje cells in the cerebellum. Ataxin-7 co localizes with full-length R85 (R85FL) in co-transfected Cos-7 cells and wi th one of the SH3P12GPs in neuronal intranuclear inclusions in brain from a SCA7 patient. We propose that this interaction is part of a physiological pathway related to the function or turnover of ataxin-7, Its role in the pa thophysiological process of SCA7 disease is discussed.