Targeting aggregation in the development of therapeutics for the treatment of Huntington’s disease and other polyglutamine repeat diseases

Abstract

Huntington’s disease (HD) is one of a number of familial polyglutamine (polyQ) repeat diseases. These neurodegenerative disorders are caused by expression of otherwise unrelated proteins that contain an expansion of a polyQ tract, rendering them toxic to specific subsets of vulnerable neurons. These expanded repeats have an inherent propensity to aggregate; insoluble neuronal nuclear and cytoplasmic polyQ aggregates or inclusions are hallmarks of the disorders [1,2]. In HD, inclusions in diseased brains often precede onset of symptoms, and have been proposed to be involved in pathogenicity [3-5]. Various strategies to block the process of aggregation have been developed in an effort to create drugs that decrease neurotoxicity. A discussion of the effect of antibodies, caspase inhibitors, chemical inhibitors, heat-shock proteins, suppressor peptides and transglutaminase inhibitors upon aggregation and disease is presented.

• aggregation
• dentatorubral-pallidoluysian atrophy (DRPLA)
• inclusion
• Huntington’s disease (HD)
• polyglutamine
• spinal and bulbar muscular atrophy (SBMA)
• spinocerebellar ataxia (SCA)