|
1 July 2002. An advanced online publication in today’s Nature Neuroscience lends support to the hypothesis that mitochondrial damage contributes to the progression of Huntington’s disease.
While it is known that a polyglutamine (polyQ) expansion in the huntingtin (htt) protein is the direct cause of this fatal disorder, just how the mutant protein wreaks havoc on neurons is poorly understood. It is thought that expanded htt, in either soluble form or in cytoplasmic or nuclear inclusions, may mediate pathogenesis by interacting with and disrupting the normal function of other proteins, such as transcription factors (see related news item). Other studies, however, have pointed out deficiencies in mitochondrial respiration in Huntington’s brain tissue, suggesting that damage to these organelles may play a role in disease progression (see Tabrizi et al.).
Timothy Greenamyre and co-workers at Emory University, Atlanta, together with colleagues from Duke University, Durham, North Carolina, and the University of British Columbia, Vancouver, now show that the membranes of mitochondria from Huntington’s patients are susceptible to depolarization. The authors used extra-organellar calcium ions to probe the mitochondrial membrane potential; if the organelles are bathed in sufficient Ca2+ the membranes will depolarize. The researchers found that much less Ca2+ was needed to achieve depolarization of lymphoblast mitochondria from HD patients than for wild-type organelles, and those from juvenile onset HD patients were even more susceptible to the cation.
First author Alexander Panov et al. repeated these experiments using brain mitochondria from transgenic mice expressing varying amounts of human mutant huntingtin, and obtained identical results. They also used electron microscopy to demonstrate that polyQ htt, but not wild-type, associates with mitochondria, suggesting that the protein may have a direct role in destabilizing their membranes, perhaps by acting as ion channels. Mitochondria are also affected in Alzheimer’s disease, (see Mungarro-Menchaca et al. 2002.)
It remains to be seen, however, whether this effect on mitochondria is a primary or secondary one, and whether it can explain the extremely slow onset of Huntington’s disease (see commentary by Elena Cattaneo below)-Tom Fagan.
Reference:
Panov AV, Gutekunst C-A, Leavitt BR, Hayden MR, Burke JR, Strittmatter WJ, Greenamyre JT. Early mitochondrial calcium defects in Huntington’s disease are a direct effect of polyglutamines. Nature Neurosci.2002 Jul 1. Abstract.
|
Home
View all comments by Elena Cattaneo
