Abstract
Mutated huntingtin (htt) is ubiquitously expressed in tissues of Huntington's disease (HD) patients. In the brain, the mutated protein leads to neuronal cell dysfunction and death, associated with formation of htt-positive inclusions. Given increasing evidence of abnormalities in HD skeletal muscle, we extensively analyzed primary muscle cell cultures from seven HD subjects (including two unaffected mutation carriers). Myoblasts from presymptomatic and symptomatic HD subjects showed cellular abnormalities in vitro, namely mitochondrial depolarization, cytochrome c release, increased caspase-3, -8, and -9 activities, and defective cell differentiation. Another notable feature was the formation of htt inclusions in differentiated myotubes. This study helps to advance current knowledge about the downstream effects of the htt mutation in human tissues. Further applications may include drug screening using this human cellular model.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / physiology*
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Caspase 3 / genetics
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Caspase 3 / metabolism
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Caspase 8 / genetics
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Caspase 8 / metabolism
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Caspase 9 / genetics
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Caspase 9 / metabolism
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Cell Differentiation / physiology
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Cells, Cultured
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Cytochromes c / genetics
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Cytochromes c / metabolism
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Gene Expression Regulation
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Gene Expression Regulation, Enzymologic
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Humans
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Huntingtin Protein
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Huntington Disease / pathology*
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Huntington Disease / physiopathology*
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Inclusion Bodies / metabolism
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Inclusion Bodies / pathology*
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Membrane Potential, Mitochondrial / physiology
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Muscle, Skeletal / chemistry
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Muscle, Skeletal / pathology*
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Muscle, Skeletal / physiopathology
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Mutation
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Myoblasts / metabolism
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Myoblasts / pathology
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism*
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
Substances
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HTT protein, human
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Huntingtin Protein
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Nerve Tissue Proteins
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Nuclear Proteins
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Cytochromes c
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Caspase 3
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Caspase 8
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Caspase 9