Introduction

Dynamic mutations in the coding region of various genes can result in human pathology, including the polyglutamine (polyQ) and polyalanine diseases. The molecular pathogenesis of the former group, comprising spinal and bulbar muscular atrophy (SBMA), dentatorubral-pallidoluysian atrophy (DRPLA), Huntington's disease (HD), and spinocerebellar ataxia (SCA) 1, 2, 3, 6, 7, and 17, has received considerable attention for more than a decade (Zoghbi and Orr 2000; Li and Li 2004a,b). Trinucleotide repeat expansion was first linked to the SBMA locus in 1991 (La Spada et al. 1991), and, 2 years later, cloning of the HD locus by a large collaboration of researchers revealed the same type of mutational event (Huntington's Disease Collaborative Research Group 1993). Although the proteins encoded by the nine polyQ disease genes do not share sequence homology outside of the polyQ domain, there is some overlap in the clinical phenotypes induced by repeat expansion. Moreover, the tendency of the expanded proteins to self-associate results in the formation of neuronal aggregates, which constitute a histopathological hallmark of the polyQ diseases. However, each polyQ disease displays selective and distinct neurodegeneration, which is not necessarily a feature of other trinucleotide repeat diseases that arise from noncoding mutations but may also affect neuronal function. Different regions of the brain or cell types within a particular structure are affected in each polyQ disease (Fig. 1). Several mechanisms have been invoked to explain the molecular pathogenesis of the polyQ diseases, including defects in both nuclear and cytoplasmic functions that are crucial to cell viability. Elucidation of the underlying molecular mechanisms will prove valuable in the development of therapeutic strategies to counter polyQ-induced neuropathology.

cortex striatum thalamus subthalamic . nucleus cortex striatum thalamus subthalamic . nucleus

spinal cord

Fig. 1 A cartoon of a sagittal brain section indicating regions that are prominently affected in the various polyglutamine (polyQ) diseases. Although degeneration in the cerebellum and brainstem is observed in all of the spinocerebellar ataxias (SCAs), the members of this subgroup can be distinguished by characteristic neuropathology within these structures. Notably, retinal degeneration occurs only in SCA7. (Modified from Ru-binsztein et al. 2002)

spinal cord

Fig. 1 A cartoon of a sagittal brain section indicating regions that are prominently affected in the various polyglutamine (polyQ) diseases. Although degeneration in the cerebellum and brainstem is observed in all of the spinocerebellar ataxias (SCAs), the members of this subgroup can be distinguished by characteristic neuropathology within these structures. Notably, retinal degeneration occurs only in SCA7. (Modified from Ru-binsztein et al. 2002)

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