Huntingtin aggregation and toxicity in Huntington's disease

Huntington's disease is a late onset neurodegenerative disorder for which the mutation is a CAG/polyglutamine (polyQ) repeat expansion in the gene encoding the huntingtin protein. The disease is one of nine inherited neurodegenerative disorders that are caused by this type of mutation, and which include dentatorubral pallidoluysian atrophy, spinal and bulbar muscular atrophy, and the spinocerebellar ataxias 1, 2, 3, 6, 7, and 17. The mutant proteins are unrelated except for the polyQ tract, and aggregated polyQ is a major component of the proteinaceous deposits that are found in patients' brains for all of these diseases.

Since the discovery of polyQ aggregates, the proposed role of the aggregation process has ranged from being central to disease pathogenesis, to a benign epiphenomenon, or even to being neuroprotective. Attempts to correlate the presence of aggregates with the onset of phenotype have been complicated by the difficulties in detecting and quantifying small aggregated forms of polyQ, and because all possible structural conformers of the repeat are present in the system under analysis. A paper by W Yang and colleagues (Hum Mol Genet 2002; 11: 2905-17) circumvents these limitations and demonstrates that preformed polyQ aggregates are highly toxic when directed to the cell nucleus. Consistent with aggregate toxicity, pharmacological intervention aimed at inhibiting aggregate formation has recently shown beneficial effects in a mouse model of Huntington's disease (I Sanchez and colleagues, Nature 2003; 421: 373-79).

The demonstration that polyQ aggregates are toxic is important because it further validates polyQ aggregation as a therapeutic target. To exploit this finding fully, greater understanding of the formation and structure of polyQ aggregates is needed. However, even without this knowledge, establishing high-throughput screens to identify aggregation inhibitors has been straightforward, and early in-vivo experiments that target aggregation have been promising. As the molecular events that contribute to the early stages of the pathogenesis of Huntington's disease are uncovered, such events will be developed as therapeutic targets. The inhibition of huntingtin aggregation should be a major focus in this effort and the practicalities of this approach are likely to unfold over the next 5-10 years.