Molecular Cloning of Murine Homologue Dentatorubral-Pallidoluysian Atrophy (DRPLA) cDNA: Strong Conservation of a Polymorphic CAG Repeat in the Murine Gene

Abstract

Eight neurodegenerative diseases are currently known to be caused by expanding polyglutamine repeats. The first to be described was spinal bulbar muscular atrophy (SBMA, or Kennedy's disease) in 1991, and the most recent addition to the list was spino-cerebellar ataxia, type 7 (SCA-7) in 1997. These disorders share a number of features. First, all cause dominantly inherited neurodegeneration in overlapping but not identical regions of the brain, resulting in overlapping clinical syndromes. Second, the causative genes have no homologies with each other except for the glutamine repeat. Third, in each disorder the length of the glutamine repeat is inversely correlated with age of disease onset, and often disease severity. Fourth, the number of glutamines in the normal (below about 35) and abnormal range (above about 35) are similar in each disorder, with the exception of SCA6. This set of findings led to the hypothesis that an abnormally long polyglutamine repeat conferred a toxic gain-of-function to each disease protein. The discovery that the abnormal protein aggregates in neuronal nuclei has suggested a plausible model of polyglutamine disease pathogenesis. This chapter reviews the evidence for this model, focusing primarily on Huntington's disease (HD), the most common and most studied of the polyglutamine disorders with an incidence of 1:10.000, and drawing on evidence from the other disorders. The data is organized according to the methods used to obtain them, a scheme which loses the historical flow, but permits direct comparison of results from the different diseases.