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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Brain / physiopathology
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Brain Chemistry
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Calcium / metabolism*
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Calcium / pharmacology
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Cell Line
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Disease Models, Animal
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Humans
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Huntingtin Protein
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Huntington Disease / etiology
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Huntington Disease / genetics
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Huntington Disease / physiopathology*
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Intracellular Membranes / chemistry
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Intracellular Membranes / metabolism
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Intracellular Membranes / ultrastructure
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Lymphocytes / chemistry
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Membrane Potentials / drug effects
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Membrane Potentials / physiology
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Mice
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Mice, Transgenic
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Microscopy, Electron
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Mitochondria / chemistry
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Mitochondria / drug effects
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Mitochondria / metabolism*
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Mitochondria / ultrastructure
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Nerve Tissue Proteins / ultrastructure
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Nuclear Proteins / ultrastructure
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Recombinant Fusion Proteins / chemistry
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Recombinant Fusion Proteins / pharmacology
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Trinucleotide Repeat Expansion
Substances
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HTT protein, human
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Htt protein, mouse
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Huntingtin Protein
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Nerve Tissue Proteins
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Nuclear Proteins
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Recombinant Fusion Proteins
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Calcium