defect in Huntington's disease

Huntington's disease (HD) is neurodegenerative illness caused by CAG triplet repeats in the gene encoding huntingtin protein (Htt), but the precise molecular mechanisms involved in the pathogenesis of the disease have remained unclear. In 1 July advanced online Nature Neuroscience, Alexander Panov and colleagues at Emory University School of Medicine, Atlanta, US, show that mutant Htt have a direct effect on mitochondria and cause mitochondrial calcium handling defects (Nat Neurosci 2002, DOI: 10.1038/nn884).

Panov et al. observed that lymphoblast mitochondria from patients with HD have a lower membrane potential and depolarize at lower calcium loads than do mitochondria from controls. They observed a similar defect in brain mitochondria from transgenic mice expressing full-length mutant huntingtin: this defect preceded the onset of pathological behavioral abnormalities by months.

In addition, they identified mutant huntingtin on neuronal mitochondrial membranes, and using a fusion protein containing an abnormally long polyglutamine repeat, they reproduced the ...