Pathogenic mechanisms of a polyglutamine-mediated neurodegenerative disease, spinocerebellar ataxia type 1

Abstract

Spinocerebellar ataxia type 1 (SCA1) is one of nine inherited neurodegenerative diseases caused by the expansion of a CAG trinucleotide repeat encoding a polyglutamine tract. SCA1 patients lose motor coordination and develop slurred speech, spasticity, and cognitive impairments. Difficulty with coordinating swallowing and breathing eventually causes death. Genetic evidence indicates that the disease mutation induces a toxic gain of function in the SCA1 encoded protein ATXN1. The discovery that residues in ATXN1 outside of the polyglutamine tract are crucial for pathogenesis hinted that alterations in the normal function of this protein are linked to its toxicity. Biochemical and genetic studies provide evidence that the polyglutamine expansion enhances interactions that are normally regulated by phosphorylation at Ser(776) and a subsequent alteration in its interaction with other cellular proteins. Moreover, the finding that other ATXN1 interactions are decreased in disease suggests that the polyglutamine expansion contributes to disease by both a gain-of-function mechanism and partial loss of function.

FIGURE 1.

Structural elements in ATXN1 that are critical for its function and pathogenesis of SCA1. The functional elements are indicated as yellow boxes. The sequence shown encompasses a full-length form of ATXN1 with 816 amino acids corresponding to a wild-type allele with 30 repeat units (residues 197–226). Wild-type alleles contain from 6 to 44 CAG repeats at this site, whereas mutant pathogenic alleles have a size range spanning 39 to 83 perfect CAG repeats. The AXH domain (residues 570–689) forms an oligonucleotide-binding fold and is important for dimerization of ATXN1 as well as its ability to interact with several proteins. The NLS (nls) spans amino acids 771–776 and targets ATXN1 to the nucleus. Finally, the C-terminal residue of the NLS, Ser⁷⁷⁶, is a site of phosphorylation in ATXN1. Phosphorylation of Ser⁷⁷⁶, as well as expansion of the polyglutamine tract, increases the interaction of ATXN1 with RBM17.

FIGURE 2.

Model of SCA1 in which expansion of the polyglutamine tract in ATXN1 shifts the balance of protein complexes. A, wild-type ATXN1 normally exists in at least two large complexes, with one containing ATXN1 that is not phosphorylated at Ser⁷⁷⁶ and CIC. The other complex contains wild-type ATXN1 phosphorylated at Ser⁷⁷⁶ associated with RBM17. B, with expansion of the polyglutamine stretch into the mutant range, the balance of these two complexes is shifted such that less ATXN1 is associated with CIC and more ATXN1 is in a complex with RBM17. The small red circles depict glutamine residues.