Polyglutamine neurodegeneration: expanded glutamines enhance native functions

Abstract

An intriguing set of neurodegenerative disease are the nine disorders caused by the expansion of a unstable trinucleotide CAG repeat where the repeat is located within the coding of the affected gene, that is, the polyglutamine (polyQ) diseases. A gain-of-function mechanism for toxicity in polyQ diseases is widely thought to have a major role in pathogenesis. Yet, the specific nature of this gain-of-function is a matter of considerable discussion. The basic issue concerns whether toxicity stems from the native or normal function of the affected protein versus a novel function induced by polyQ expansion. For at least three of the polyQ disease considerable evidence is accumulating that pathology is mediated by a polyQ-induced exaggeration of a native function of the host protein.

Figure 1. Schematic Depiction of the Minimum Elements of the Native Ligand-Dependent AR Pathway Required for Pathogenesis

To induce pathogenesis AR with an expanded polyQ must (1) Ligand binds to AR inducing a conformation change that releases the bound chaperone, uncovers the NLS and creates the AF-2 binding surface. Presumably mutant AR forms a dimer prior to (2) AR and bound ligand translocate to the nucleus. (3) AR and bound ligand bind to DNA targets sites. (4) AF-2 interacting co-regulators bind. It remains unclear the extent to which if any downstream events (depicted by dashed lines) such as target gene transcription and subsequent steps contribute to pathogenesis.

Figure 2. A Hypothesis in which the Consequence of Expanded PolyQ is to Enhance a Native Function

Normally the polyQ host exists in a equilibrium of multiple conformations each of which sub serves a native function. Upon expansion of the polyQ (red shaded portion) one native conformation predominates and its associated function is now enhanced in a disease-specific manner.