Chaperones in Polyglutamine Aggregation: Beyond the Q-Stretch.

E F E Kuiper,Harm H Kampinga,Eduardo P De Mattos,Laura B Jardim,Steven Bergink

doi:10.3389/fnins.2017.00145

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.

Highlights

Polyglutaminopathies are a family of diseases characterized by CAG trinucleotide expansions in the coding regions of at least nine unrelated genes, resulting in proteins with an abnormally long polyglutamine stretch, which have a high aggregation propensity
Chaperones in Polyglutamine Aggregation: Beyond the Q-stretch higher aggregation proneness of the affected protein, indicating that an expanded polyQ is tightly related to the diseases
Next to aggregation of the core polyQ stretch, which is common to all polyglutaminopathies (Figure 2A), the context around the cores can modulate aggregation in several ways and may be linked to differential handling of the protein quality control systems, including molecular chaperones, the ubiquitin proteasome system, and autophagy

Summary

INTRODUCTION

Polyglutaminopathies are a family of diseases characterized by CAG trinucleotide expansions in the coding regions of at least nine unrelated genes, resulting in proteins with an abnormally long polyglutamine (polyQ) stretch, which have a high aggregation propensity. Next to aggregation of the core polyQ stretch, which is common to all polyglutaminopathies (Figure 2A), the context around the cores can modulate aggregation in several ways and may be linked to differential handling of the protein quality control systems, including molecular chaperones, the ubiquitin proteasome system, and autophagy. Rather than providing a complete overview, molecular mechanisms of typical examples will be discussed, aiming at providing general principles affecting polyQ aggregation on FIGURE 1 | Age of onset of disease inversely correlates with the size of the expanded polyQ tract in all known polyQ diseases. The molecular level that may partially explain the individual differences between patients and steer future studies

POLYQ STRETCH

AGGREGATION INITIATION BY FLANKING

INFLUENCE AGGREGATION