Cell biology of spinocerebellar ataxia

Abstract

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.

Figure 1.

An ATXN1 cellular pathway. ATXN1 is phosphorylated at S776 in the cytoplasm upon which it forms a complex with 14-3-3. Association with 14-3-3 blocks dephosphorylation of pS776 and transport of ATXN1 to the nucleus. Thus, nuclear transport of ATXN1 requires dissociation from 14-3-3, the regulation of which has yet to be determined. In the nucleus, ATXN1 is involved in alternative splicing by virtue of its interaction with RBM17 when phosphorylated on S776, or with U2AF65 after dephosphorylation of pS776. ↑[Q]_n indicates that an increased interaction of expanded polyQ ATXN1 with RBM17 is hypothesized to be critical for driving disease in cerebellar Purkinje cells.

Figure 2.

Proposed functions of ATXN2 in the regulation of mRNA translation. The SCA2-encoded protein, ATXN2, is thought to have a role in mRNA metabolism as a component of translating polysomes, cytoplasmic stress granules, P-bodies, and the miRNA pathway. One intriguing possibility would be for ATXN2 to function in the trafficking of RNA/RNPs between actively translating polysomes and inactive stress granules and P-bodies.

Figure 3.

A model for ATXN3 in the editing of Ub chains on nuclear targets. The model combines the recent work of Scaglione et al. (2011) with earlier studies showing that ATXN3, a deubiquitinating enzyme, has a role in regulating gene expression. Like the proposed role of ATXN3 in the Ube2W/CHIP ubiquitination cycle of misfolded proteins, it is postulated that ATXN3 also regulates a ubiquitination cycle involved in assembly/disassembly of transcription complexes in the nucleus. ↑[Q]_n indicates an increased interaction of expanded polyQ ATXN3 with a yet to be identified nuclear protein involved in regulation of transcription.