A study published yesterday in the online Annals of Neurology provides a glimpse at the complexity involved in the time- and cell-specific neurodegeneration of Huntington's disease. Ole Isacson and his colleagues at Harvard University report that ubiquitin proteasome system (UPS) dysfunction occurs in many unaffected areas of brain, and even in skin, as well as both early and late in the disease.

Even though huntingtin—whether normal or mutated—is ubiquitously expressed throughout the body, only striatum (caudate and putamen) and cortex sustain substantial and progressive cell loss in HD. While there is a brain region- and time-specific accumulation of intracellular expanded polyQ huntingtin, this is not fully paralleled by cell loss or disease symptoms. In trying to understand the specific susceptibility of striatal and cortical cells to the huntingtin mutation, first author Hyemyung Seo, Kai-Christian Sonntag, and Isacson set their sights on the UPS, following up earlier suggestions that defects in this proteolytic recycling system could underlie the accumulation and toxicity of the polyQ huntingtin.

Surprisingly, the authors found comparably reduced UPS activity in human postmortem tissue whether the huntingtin mutation carriers had died with severe disease and brain pathology or whether they died of other causes with little or no pathology. These proteasome system deficits were seen not only in the caudate-putamen and cortex, but also in substantia nigra and cerebellum. Perhaps even more surprising, the researchers found UPS inhibition in skin fibroblasts from HD patients. There was one UPS system abnormality specific to striatum, however: Late in HD, ubiquitin levels were increased in this brain area.

The apparently generalized inhibition of proteasomes in HD was supported by an experiment wherein the proteasome activator PA28 was expressed in fibroblasts via a viral vector. PA28 was able to increase UPS activity in normal but not HD cells.

Moving to other candidate mechanisms in HD, Seo and colleagues found that BDNF levels were also decreased in all sampled HD brain regions at both early and late disease stages. However, reductions in mitochondrial metabolic complex II/III activity were found only in the striatum, both in early and late disease.

So the HD plot thickens, it would seem. "It is likely that an effective prevention or protection against huntingtin pathology needs to improve several cellular functions, unless the treatment completely eliminates the pathogenic form of huntingtin, or its effects in vulnerable cells," the authors conclude.—Hakon Heimer


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Primary Papers

  1. . Generalized brain and skin proteasome inhibition in Huntington's disease. Ann Neurol. 2004 Sep;56(3):319-28. PubMed.