Polyglutamine Repeats in Neurodegenerative Diseases

Abstract

Among the age-dependent protein aggregation disorders, nine neurodegenerative diseases are caused by expansions of CAG repeats encoding polyglutamine (polyQ) tracts. We review the clinical, pathological, and biological features of these inherited disorders. We discuss insights into pathogenesis gleaned from studies of model systems and patients, highlighting work that informs efforts to develop effective therapies. An important conclusion from these analyses is that expanded CAG/polyQ domains are the primary drivers of neurodegeneration, with the biology of carrier proteins influencing disease-specific manifestations. Additionally, it has become apparent that CAG/polyQ repeat expansions produce neurodegeneration via multiple downstream mechanisms, involving both gain- and loss-of-function effects. This conclusion indicates that the likelihood of developing effective therapies targeting single nodes is reduced. The evaluation of treatments for premanifest disease will likely require new investigational approaches. We highlight the opportunities and challenges underlying ongoing work and provide recommendations related to the development of symptomatic and disease-modifying therapies and biomarkers that could inform future research.

Keywords: Huntington's disease; neurodegeneration; polyglutamine; spinal and bulbar muscular atrophy; spinocerebellar ataxia; trinucleotide repeat disorders.

Figure 1.

Microsatellite repeat expansion diseases. Microsatellite expansions of reiterated sequences of varying length occur in coding and non-coding regions of genes to cause human disease. Non-coding repeat expansions occur in 5’ or 3’ UTRs or introns and may encode thousands of repeated units. Coding region microsatellite expansions are restricted to trinucleotide repeats and tend to be more modest in length compared with non-coding region expansions. (Adapted from ref 150a).