Abstract
In patients with Huntington's disease (HD), the proteolytic activity of the ubiquitin proteasome system (UPS) is reduced in the brain and other tissues. The pathological hallmark of HD is the intraneuronal nuclear protein aggregates of mutant huntingtin. We determined how to enhance UPS function and influence catalytic protein degradation and cell survival in HD. Proteasome activators involved in either the ubiquitinated or the non-ubiquitinated proteolysis were overexpressed in HD patients' skin fibroblasts or mutant huntingtin-expressing striatal neurons. Following compromise of the UPS, overexpression of the proteasome activator subunit PA28gamma, but not subunit S5a, recovered proteasome function in the HD cells. PA28gamma also improved cell viability in mutant huntingtin-expressing striatal neurons exposed to pathological stressors, such as the excitotoxin quinolinic acid and the reversible proteasome inhibitor MG132. These results demonstrate the specific functional enhancements of the UPS that can provide neuroprotection in HD cells.
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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Cell Survival
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Cells, Cultured / cytology
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Cells, Cultured / metabolism
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Corpus Striatum / pathology
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Fibroblasts / metabolism
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Fibroblasts / pathology
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Humans
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Huntingtin Protein
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Huntington Disease / pathology*
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Leupeptins / pharmacology
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Muscle Proteins / genetics
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Muscle Proteins / physiology*
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Neurons / metabolism
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Neurons / pathology*
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Nitro Compounds / pharmacology
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Peptide Fragments / genetics
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Peptide Fragments / metabolism
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Propionates / pharmacology
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Proteasome Endopeptidase Complex / drug effects
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Proteasome Endopeptidase Complex / genetics
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Proteasome Endopeptidase Complex / metabolism*
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Proteasome Endopeptidase Complex / physiology
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Quinolinic Acid / pharmacology
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RNA-Binding Proteins
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Recombinant Fusion Proteins / physiology
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Transduction, Genetic
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Ubiquitin / metabolism
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Up-Regulation
Substances
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HTT protein, human
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Huntingtin Protein
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Leupeptins
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Muscle Proteins
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Nerve Tissue Proteins
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Nitro Compounds
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Nuclear Proteins
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PSMD4 protein, human
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PSME1 protein, human
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Peptide Fragments
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Propionates
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RNA-Binding Proteins
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Recombinant Fusion Proteins
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Ubiquitin
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Proteasome Endopeptidase Complex
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proteasome activator PA700 subunit p58, human
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Quinolinic Acid
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3-nitropropionic acid
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde