Abstract
Misfolded proteins accumulate in many neurodegenerative diseases, including huntingtin in Huntington's disease and alpha-synuclein in Parkinson's disease. The disease-causing proteins can take various conformations and are prone to aggregate and form larger cytoplasmic or nuclear inclusions. One approach to the development of therapeutic intervention for these diseases has been to identify chemical compounds that reduce the size or number of inclusions. We have, however, identified a compound that promotes inclusion formation in cellular models of both Huntington's disease and Parkinson's disease. Of particular interest, this compound prevents huntingtin-mediated proteasome dysfunction and reduces alpha-synuclein-mediated toxicity. These results demonstrate that compounds that increase inclusion formation may actually lessen cellular pathology in both Huntington's and Parkinson's diseases, suggesting a therapeutic approach for neurodegenerative diseases caused by protein misfolding.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Base Sequence
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CHO Cells
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Cell Line
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Cricetinae
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DNA, Recombinant / genetics
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Genes, Reporter
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Green Fluorescent Proteins / genetics
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Green Fluorescent Proteins / metabolism
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Humans
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Huntingtin Protein
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Huntington Disease / drug therapy*
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Huntington Disease / metabolism
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Huntington Disease / pathology
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In Vitro Techniques
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Inclusion Bodies / drug effects*
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Inclusion Bodies / metabolism
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Inclusion Bodies / pathology
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Nerve Tissue Proteins / chemistry
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Nerve Tissue Proteins / drug effects
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Nerve Tissue Proteins / genetics
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Nuclear Proteins / chemistry
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Nuclear Proteins / drug effects
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Nuclear Proteins / genetics
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Parkinson Disease / drug therapy*
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Parkinson Disease / metabolism
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Parkinson Disease / pathology
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Piperazines / pharmacology*
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Proteasome Endopeptidase Complex / metabolism
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Protein Folding
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Quinolines / pharmacology*
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Recombinant Fusion Proteins / chemistry
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Recombinant Fusion Proteins / drug effects
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Recombinant Fusion Proteins / genetics
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alpha-Synuclein / toxicity
Substances
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DNA, Recombinant
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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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Piperazines
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Quinolines
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Recombinant Fusion Proteins
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alpha-Synuclein
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enhanced green fluorescent protein
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Green Fluorescent Proteins
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Proteasome Endopeptidase Complex