The cell biology of disease Cell biology of spinocerebellar ataxia

Correspondence to Harry T. Orr: [email protected] Abbreviations used in this paper: ALS, amyotrophic lateral sclerosis; ATXN, ataxin; CHIP, C terminus of Hsc70-interacting protein; DUB, deubiquitinating enzyme; NLS, nuclear localization sequence; polyQ, polyglutamine; SCA, spinocerebellar ataxia. Individuals suffering from ataxia are at first clumsy and unable to walk steadily, and have slurred speech. Patients can eventually lose the ability to swallow and breathe in a coordinated fashion, which can be fatal. Ataxia results from variable degeneration of neurons in the cerebellum, brain stem, spinocerebellar tracts, and their afferent/efferent connections. Such neurodegenerations can be due to a variety of clinical conditions, including multiple sclerosis, a brain tumor, alcoholism, or an inherited genetic defect. There are over 50 different forms of inherited ataxias that strike during childhood or adulthood (Taroni and DiDonato, 2004; Manto, 2005). Among the inherited forms of ataxia are several recessive forms of ataxia that include Friedreich ataxia—the most common inherited form of ataxia that affects mitochondrial function, AVED ataxia due to vitamin E deficiency, and ataxia telangiectasia affecting regulation of the cell cycle. Spinocerebellar ataxias, or SCAs, are inherited in an autosomal-dominant pattern. There are 30 different types of SCA identified to date but causative mutations have been identified for only half of them. Among these are the ataxias caused by mutations in protein kinase C (SCA14) and fibroblast growth factor 14. Most of the SCAs are caused by an abnormal expansion of a CAG repeat sequence that encodes for an expanded tract of polyglutamine (polyQ) residues within the mutated protein. It is the polyQ SCAs that are the subject of this review. The cellular and molecular mechanisms responsible for pathogenesis of the polyQ neurodegenerative diseases are a matter of spirited discussions. For the most part these discussions center on two major points. The first focuses on to what extent the polyglutamine tract alone drives pathogenesis. It is clear that expanded polyQ peptides are toxic, with early studies indicating that disease might stem from the proteolytic production of such peptides (Marsh et al., 2000). Yet, only for Huntington’s disease is there evidence that proteolytic cleavage and the generation of a toxic polyQ peptide might be required for pathogenesis (Davies et al., 1997; DiFiglia et al., 1997; Graham et al., 2006). The second point is whether the tendency of mutant polyQ proteins to aggregate is responsible for the disease-associated neurodegeneration. PolyQ expansion renders the protein more prone to aggregation and formation of inclusion bodies that are a pathological hallmark of these disorders including the polyQ SCAs (Orr and Zoghbi, 2007). Yet, the extent to which these inclusions cause disease continues to be a complex issue. There are several studies demonstrating that in mouse models disease severity can be disassociated from presence of inclusions (Klement et al., 1998; Saudou et al., 1998; Cummings et al., 1999), Moreover, there are data indicating that inclusions may be protective, perhaps by sequestration of the mutant protein (Cummings et al., 1999; Arrasate et al., 2004; Bowman et al., 2007). More recent studies in both patients and model systems support the concept that the native/normal functions of the polyQ proteins are required for development of disease. Most notably, in the polyQ disease spinobulbar muscular atrophy (SBMA), where disease is caused by a polyQ expansion in the androgen receptor (La Spada et al., 1991), both androgen binding and nuclear translocation of mutant androgen receptor are required for development of the SBMA-associated motor neuron disease (Katsuno et al., 2002; Takeyama et al., 2002; Nedelsky et al., 2010). Moreover, disruption of androgen receptor interaction Ataxia is a neurological disorder characterized by loss of control of body movements. Spinocerebellar ataxia (SCA), previously known as autosomal dominant cerebellar ataxia, is a biologically robust group of close to 30 progressive neurodegenerative diseases. Six SCAs, including the more prevalent SCA1, SCA2, SCA3, and SCA6 along with SCA7 and SCA17 are caused by expansion of a CAG repeat that encodes a polyglutamine tract in the affected protein. How the mutated proteins in these polyglutamine SCAs cause disease is highly debated. Recent work suggests that the mutated protein contributes to pathogenesis within the context of its “normal” cellular function. Thus, understanding the cellular function of these proteins could aid in the development of therapeutics. The cell biology of disease