Therapeutic perspectives for the treatment of Huntington's disease: treating the whole body

Abstract

Huntington's disease (HD) is a tremendously debilitating disorder that strikes relatively young individuals and progresses rapidly over the next ten to fifteen years inducing a loss of cognitive and motor skills and eventually death occurs. The primary locus of the disorder is a polyglutamine expansion of the protein product of the huntingtin (htt) gene. The htt protein appears to be a scaffolding protein that orchestrates the complex assembly of multiple intracellular proteins involved in multiple processes, including vesicular movement and cell metabolism. The htt protein is ubiquitously expressed in human tissues but the predominance of the interest in the pathology lies in its effects on the central nervous system (CNS). Most of the current therapeutics for HD thus have been targeted at preventing neuronal damage in the CNS, however, a considerable body of evidence has been accumulating to suggest that the maintenance of a healthy nervous system is tightly linked with peripheral physiological health. Therefore treatment of both the peripheral and central pathophysiologies of HD could form the basis of a more effective HD therapeutic strategy.

Fig. 1

Brief schematic overview of the some of the potential peripheral (mostly shown in murine HD models) and central nervous system (CNS) deficits in Huntington’s disease. The CNS effects include cognitive and psychological problems, neuronal intranuclear inclusions (NIIs) and mutant huntingtin protein (htt) aggregates in the cortex and striatum, and motor dysfunction. The peripheral effecs include mitochondrial dysfunction and oxidative stress, muscular rigidity, alteration in appetite, pancreatic dysfunction and imparied energy metabolism.