Spinocerebellar ataxia type 7 (SCA7) is one member of a growing list of
neurodegenerative disorders that are all caused by CAG repeat expansions that produce disease by encoding elongated
polyglutamine tracts in a variety of apparently unrelated
proteins. In this review, we provide an overview of our efforts to determine the molecular basis of
polyglutamine neurotoxicity in SCA7 by modeling this
polyglutamine repeat disorder in mice. We discuss how our SCA7 mouse model develops a phenotype that is reminiscent of the
retinal and
cerebellar disease pathology seen in human patients. All of these findings are considered in the context of numerous other models of
polyglutamine disease pathology in mice and other organisms, together with various other in vitro and biochemical studies. We present the competing hypotheses of
polyglutamine disease pathogenesis, and explain how our studies of SCA7 brainstem and
retinal degeneration using this mouse model have yielded insights into possible mechanisms and pathways of
polyglutamine disease pathology. In addition to illustrating how our SCA7 mouse model has allowed us to develop and advance notions of disease pathogenesis, we propose a model of
polyglutamine molecular pathology that attempts to integrate the key observations in the field. We close by describing why our SCA7 mouse model should be useful for the next phase of
polyglutamine disease research--the development of
therapies, and predict that this stage of experimentation will continue to rely heavily on the mouse.