Early mitochondrial calcium defects in Huntington's disease are a direct effect of polyglutamines

Abstract

Huntington's disease (HD) is caused by an expansion of exonic CAG triplet repeats in the gene encoding huntingtin protein (Htt), but the mechanisms by which this mutant protein causes neurodegeneration remain unknown. Here we show that lymphoblast mitochondria from patients with HD have a lower membrane potential and depolarize at lower calcium loads than do mitochondria from controls. We found a similar defect in brain mitochondria from transgenic mice expressing full-length mutant huntingtin, and this defect preceded the onset of pathological or behavioral abnormalities by months. By electron microscopy, we identified N-terminal mutant huntingtin on neuronal mitochondrial membranes, and by incubating normal mitochondria with a fusion protein containing an abnormally long polyglutamine repeat, we reproduced the mitochondrial calcium defect seen in human patients and transgenic animals. Thus, mitochondrial calcium abnormalities occur early in HD pathogenesis and may be a direct effect of mutant huntingtin on the organelle.

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Figure 1: Mitochondrial abnormalities in lymphoblasts from HD patients.
Figure 2: Brain mitochondrial abnormalities in transgenic mice expressing mutant Htt.
Figure 3: Kinetic traces of mitochondrial Ca2+ uptake and release.
Figure 4: Immunocytochemistry of N-terminal Htt in brain mitochondria of YAC18 and YAC72 transgenic mice.
Figure 5: A fusion protein containing a polyglutamine tract of 62 residues reduced the Ca2+ retention capacity of normal lymphoblast mitochondria, but a fusion protein with a polyglutamine length of 19 (GST-Q19) did not.

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Acknowledgements

This work was supported by the Huntington's Disease Society of America's Coalition for the Cure program (A.V.P., C.A.G., B.R.L., M.R.H. and J.T.G.), the Hereditary Disease Foundation (M.R.H.), the Huntington Society of Canada (M.R.H. and B.R.L.), a Canada Research Chair (M.R.H.), the Canadian Institutes of Health Research (M.R.H. and B.R.L.) and a National Institutes of Health grant AG14648 (J.T.G. and A.V.P.).

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Correspondence to J. Timothy Greenamyre.

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Panov, A., Gutekunst, C., Leavitt, B. et al. Early mitochondrial calcium defects in Huntington's disease are a direct effect of polyglutamines. Nat Neurosci 5, 731–736 (2002). https://doi.org/10.1038/nn884

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