Animal models of polyglutamine diseases and therapeutic approaches

Abstract

The dominant gain-of-function polyglutamine repeat diseases, in which the initiating mutation is known, allow development of models that recapitulate many aspects of human disease. To the extent that pathology is a consequence of disrupted fundamental cellular activities, one can effectively study strategies to ameliorate or protect against these cellular insults. Model organisms allow one to identify pathways that affect disease onset and progression, to test and screen for pharmacological agents that affect pathogenic processes, and to validate potential targets genetically as well as pharmacologically. Here, we describe polyglutamine repeat diseases that have been modeled in a variety of organisms, including worms, flies, mice, and non-human primates, and discuss examples of how they have broadened the therapeutic landscape.

FIGURE 1.

Structures of polyQ disease proteins. The polyQ expansion is indicated by inverted wedges. The polyQ repeat size in normal individuals is adjacent to the unshaded portion, with disease range expansion in the shaded portion. Arrows above the diagram indicate the smallest claimed pathogenic fragments (10, 12, 19). aa, amino acids; MJD, Machado-Joseph disease; TBP, TATA-binding protein.