From pathways to targets: understanding the mechanisms behind polyglutamine disease

Abstract

The history of polyglutamine diseases dates back approximately 20 years to the discovery of a polyglutamine repeat in the androgen receptor of SBMA followed by the identification of similar expansion mutations in Huntington's disease, SCA1, DRPLA, and the other spinocerebellar ataxias. This common molecular feature of polyglutamine diseases suggests shared mechanisms in disease pathology and neurodegeneration of disease specific brain regions. In this review, we discuss the main pathogenic pathways including proteolytic processing, nuclear shuttling and aggregation, mitochondrial dysfunction, and clearance of misfolded polyglutamine proteins and point out possible targets for treatment.

Figure 1

A model of the common molecular mechanisms behind polyglutamine pathology. Schematic illustration of the intracellular fate of the polyglutamine (polyQ) expanded protein, from the unprocessed mutant protein to a protein aggregate. The mutant protein (a) is proteolytically processed by endogenous enzymes (b) forming toxic fragments (c). These fragments form aggregates in the cytoplasm (d). Alternatively, toxic breakdown products can translocate into the nucleus (e) and generate nuclear aggregates (h) by forming intermediate species (f) and sequestering further vital proteins (g). Accumulation of polyQ species can damage important cellular components and lead, for example, to mitochondrial dysfunction (i). The visualized pathways point possible sites for therapeutic engagement: prevention of proteolytic events (I) can decrease levels of toxic fragments. Alteration of nuclear shuttling (II) and modulation of aggregation (III) can ameliorate the detrimental effects of toxic species. As polyQ expansions lead to misfolded proteins, structural refolding assisted by enhanced chaperone activity (IV) might be beneficial. An increased degradation of polyQ proteins and aggregates via proteasomal (V), lysosomal (VI), and autophagosomal (VII) pathways can reduce the amounts of toxic species inside the cell. Finally, attenuating the consequences of polyQ toxicity (VIII), like impaired mitochondrial function, can improve the cellular viability.