Abstract
Huntington's disease (HD), with its selective neuronal cell loss, is caused by an elongated glutamine tract in the huntingtin protein. To discover the pathways that are candidates for the protein's normal and/or abnormal function, we surveyed 19 classes of organelle in Hdh(ex4/5)/Hdh(ex4/5) knock-out compared with wild-type embryonic stem cells to identify any that might be affected by huntingtin deficiency. Although the majority did not differ, dramatic changes in six classes revealed that huntingtin's function is essential for the normal nuclear (nucleoli, transcription factor-speckles) and perinuclear membrane (mitochondria, endoplasmic reticulum, Golgi and recycling endosomes) organelles and for proper regulation of the iron pathway. Moreover, upmodulation by deferoxamine mesylate implicates huntingtin as an iron-response protein. However, excess huntingtin produced abnormal organelles that resemble the deficiency phenotype, suggesting the importance of huntingtin level to the protein's normal pathway. Thus, organelles that require huntingtin to function suggest roles for the protein in RNA biogenesis, trafficking and iron homeostasis to be explored in HD pathogenesis.
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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Active Transport, Cell Nucleus / drug effects
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Animals
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Carrier Proteins / physiology
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Cell Nucleus / drug effects
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Cell Nucleus / genetics
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Cell Nucleus / pathology
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Cell Nucleus / ultrastructure
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Endoplasmic Reticulum / pathology
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Endosomes / pathology
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Exportin 1 Protein
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Fatty Acids, Unsaturated / pharmacology
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Gene Deletion
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Gene Expression
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Golgi Apparatus / pathology
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Humans
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Huntingtin Protein
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Huntington Disease / genetics*
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Huntington Disease / metabolism
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Intracellular Membranes / pathology
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Intracellular Membranes / ultrastructure
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Iron / metabolism*
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Karyopherins*
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Mice
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Mice, Knockout
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Mitochondria / genetics
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Mitochondria / pathology
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Mitochondria / ultrastructure
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Nerve Tissue Proteins / deficiency
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism*
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Nuclear Proteins / deficiency
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Organelles / genetics
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Organelles / pathology*
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Organelles / ultrastructure
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Phenotype
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RNA / biosynthesis
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RNA / genetics
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Receptors, Cytoplasmic and Nuclear*
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Receptors, Transferrin / metabolism
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Stem Cells / metabolism
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Stem Cells / pathology
Substances
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Carrier Proteins
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Fatty Acids, Unsaturated
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HTT protein, human
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Htt protein, mouse
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Huntingtin Protein
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Karyopherins
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Nerve Tissue Proteins
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Nuclear Proteins
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Receptors, Cytoplasmic and Nuclear
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Receptors, Transferrin
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RNA
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Iron
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leptomycin B