Credit: Courtesy of Jim P. Dompierre

Mutations in just one gene, encoding the protein huntingtin, underlie Huntington disease, but the pathogenic mechanisms are unclear. Two recent studies dissect the molecular underpinnings of this polyglutamine disorder.

In the 9 July 2004 issue of Cell (118, 127–138), Laurent Gauthier and Bénédicte Charrin et al. examine whether the disease is caused by the loss of huntingtin function. They find that the wild-type protein enhanced the microtubule-mediated transport of a molecule that supports neuronal survival, brain-derived neurotrophic factor (BDNF; huntingtin in red, BDNF in green in the figure). This effect involved interactions of huntingtin with huntingtin-associated protein (HAP-1) and the molecular motor dynactin. The authors showed that mutant huntingtin failed to transport BDNF properly along nerve fibers, leading to neuronal cell death. Previous work had implicated huntingtin in neuronal survival; this work fleshes out the mechanism.

In the 2 July 2004 issue of Molecular Cell (15, 95–105), Gregor Schaffar and Peter Breuer et al. examine whether the pathogenic mechanism depends on the toxicity of the mutant huntingtin. They report that expanded polyglutamine repeats in mutant huntingtin inhibit the function of a native polyglutamine repeat–containing protein, the transcription factor TBP. Polyglutamine repeats in Huntington disease and related disorders have a reputation for affecting native polyglutamine-containing proteins; this could happen by sequestration in polyglutamine-containing nuclear inclusions. Instead, the authors found that the repeats interacted with TBP independent of the formation of insoluble aggregates, and that the HSP70/HSP40 molecular chaperones interfered with this process. As both studies were performed in culture, the relative contribution of these phenomena to disease remains to be established in vivo.