Polyglutamine neurodegenerative diseases and regulation of transcription: assembling the puzzle

Abstract

The polyglutamine disorders are a class of nine neurodegenerative disorders that are inherited gain-of-function diseases caused by expansion of a translated CAG repeat. Even though the disease-causing proteins are widely expressed, specific collections of neurons are more susceptible in each disease, resulting in characteristic patterns of pathology and clinical symptoms. One hypothesis poses that altered protein function is fundamental to pathogenesis, with protein context of the expanded polyglutamine having key roles in diseasespecific processes. This review will focus on the role of the disease-causing polyglutamine proteins in gene transcription and the extent to which the mutant proteins induce disruption of transcription.One of the intriguing developments in human genetics is the identification of a mutational mechanism apparently unique to the human genome, the expansion of unstable nucleotide repeats (Gatchel and Zoghbi 2005). Depending on the genetic context of the unstable repeat, the pathogenic mechanism underlying the disorder can be either a loss-of-function or gain-of-function mutation operating at either the RNA or protein level. A subclass of the unstable repeat disorders is caused by the expansion of an unstable CAG trinucleotide repeat located within the protein encoding region such that the repeat is translated into a stretch of glutamine residues; i.e., the polyglutamine diseases. Although rare as a group, the polyglutamine disorders represent the most common form of inherited neurodegenerative disease. At present, nine disorders make up this class of neurodegenerative disease (Table 1). Initially, it was argued that the genetic similarities among these disorders strongly supported the hypothesis that these disorders shared a common mechanism of pathogenesis entirely dependent on the toxic properties of the polyglutamine tract. This typically centered on the enhanced ability of polyglutamine peptides to form intranuclear aggregates/inclusions (Ross and Poirer 2004). The presence of these aggregates/ inclusions within the nuclei of affected neurons focused attention on the nucleus as the subcellular site important in pathogenesis. After much study, the concept of large aggregates/inclusions of mutant polyglutamine as the pathogenic species has become suspect (Arrasate et al. 2004). However, for many of the polyglutamine disorders, understanding events in the nucleus still remains crucial for comprehending pathogenesis.Expansion of the polyglutamine tract is the trigger for pathogenesis. Yet, it likely does so by acting in concert with the other amino acids of the "host" protein (Orr 2001). This point is nicely illustrated by studies on SCA1 and AR/SBMA. In the case of SCA1, replacing single amino acids in ataxin-1 outside of its polyglutamine tract dramatically reduced the ability of mutant ataxin-1 (ataxin-1[82Q]) to cause disease in vivo (Klement et al. 1998;Emamian et al. 2003). In SBMA, androgen binding to the ligand-binding region in AR is critical for pathogenesis (Katsuno et al. 2002(K...

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