Chaperones in Polyglutamine Aggregation: Beyond the Q-Stretch

Abstract

Expanded polyglutamine (polyQ) stretches in at least nine unrelated proteins lead to inherited neuronal dysfunction and degeneration. The expansion size in all diseases correlates with age at onset (AO) of disease and with polyQ protein aggregation, indicating that the expanded polyQ stretch is the main driving force for the disease onset. Interestingly, there is marked interpatient variability in expansion thresholds for a given disease. Between different polyQ diseases the repeat length vs. AO also indicates the existence of modulatory effects on aggregation of the upstream and downstream amino acid sequences flanking the Q expansion. This can be either due to intrinsic modulation of aggregation by the flanking regions, or due to differential interaction with other proteins, such as the components of the cellular protein quality control network. Indeed, several lines of evidence suggest that molecular chaperones have impact on the handling of different polyQ proteins. Here, we review factors differentially influencing polyQ aggregation: the Q-stretch itself, modulatory flanking sequences, interaction partners, cleavage of polyQ-containing proteins, and post-translational modifications, with a special focus on the role of molecular chaperones. By discussing typical examples of how these factors influence aggregation, we provide more insight on the variability of AO between different diseases as well as within the same polyQ disorder, on the molecular level.

Keywords: Huntington's disease; Machado-Joseph disease; aggregation; molecular chaperones; polyglutamine disease.

Figure 1

Age of onset of disease inversely correlates with the size of the expanded polyQ tract in all known polyQ diseases. (A) Correlation between age of onset (AO) and CAG expansion size for all nine polyQ diseases identified so far. Circles depict mean AOs for a given expansion size based on multiple reported cohorts of patients. Lines represent the fitted data according to an exponential decay model. (B) Age of onset of disease is not completely determined by the expanded polyQ tract alone. Data on the variability of AO for a particular polyQ expansion size is shown as in (A) and was based on the large cohort of MJD/SCA3 patients reported by Saute and Jardim (2015). Circles represent single patients. Please refer to Supplementary File 1 for a complete list of references of the original cohort descriptions. Note that graph (A,B) are not drawn to the same scale.

Figure 2

Representation of pathogenic polyQ proteins and known modulating events associated with aggregation. (A) Schematic representation of the nine disease-related polyglutamine proteins drawn to scale. In each case, a polyQ stretch of fixed length is depicted at the approximate position (red boxes). Red bars on the right side of each protein show the smallest and largest number of glutamine repeats identified in patients of each polyQ disease to date. Numbers between brackets represent polyQ expansion sizes that have been reported to behave as incomplete penetrance alleles. (B) Detailed representation of all nine polyQ proteins. Domain organization is indicated. Known post-translational modifications associated with disease, caspase/calpain cleavage sites, and fragments identified are indicated. For ataxin-3, the long isoform with 3 ubiquitin-interacting motifs is shown. Residues C14, H119, and N134 depict the catalytic triad of the deubiquitylase activity of the Josephin domain. The CACNA1A locus encodes two proteins: α1A (full-length α1A) and α1ACT (C-terminal fragment of α1A) using a bicistronic mRNA with a cryptic internal ribosomal entry site. The polyQ is found in both. Many studies report a C-terminal fragment which probably represents α1ACT. For the androgen receptor, the only phosphorylation sites depicted are those with biochemical evidence of modulation of polyQ aggregation, cleavage and/or toxicity. Similarly, amino acid sequences 23FQNLF27 and 55LLLL58 highlight motifs shown to influence polyQ behavior. For simplicity, most huntingtin cleavage products are omitted and only the major N-terminal polyQ containing fragment is indicated. Amino acid numbering is based on Uniprot accession numbers P42858 (HTT), P54253 (ATXN1), Q99700 (ATXN2), P54252 (ATXN3), O00555 (CACNA1A), O15265 (ATXN7), P20226 (TBP), P54259 (ATN1), and P10275 (AR). However, for clarity, some residues are numbered according to their original publication, which might differ from the numbering according to the reference protein sequence (due to the expanding nature of polyQ proteins). AR, androgen receptor; ATN1, atrophin-1; ATXN1, ataxin-1; ATXN2, ataxin-2; ATXN3, ataxin-3; ATXN7, ataxin-7; AXH, ataxin-1/high-mobility group box containing protein-1; CACNA1, α1A subunit of the P/Q-type or CaV2.1 voltage-gated calcium channel; Casp, caspase; DBD, DNA binding domain; HTT, huntingtin; PolyQ, polyglutamine stretch; NTD/AF-1, amino-terminal domain/ activation function-1; LBD/AF-2, ligand-binding domain/ activation function-2; NES, nuclear export signal; NLS, nuclear localization signal; HEAT, huntingtin/elongation factor 3/PR65/A subunit of protein phosphatase 2A/ lipid kinase TOR domain; PRR, proline-rich region; N17, first 17 amino acids of huntingtin; TBP, TATA-binding protein (domain); UIM, ubiquitin-interacting motif; Ub-1/Ub2, ubiquitin-binding sites; Lsm, Like RNA splicing domain Sm and Sm2; LsmAD, Like-Sm-associated domain; PAM2, poly (A)-binding protein interacting motif 2; ZnF, SCA7-like zinc finger domain. For references to specific domains or post-translational modifications, please refer to Supplementary File 1.