Abstract
The accumulation of alpha-synuclein, ubiquitin and other proteins in Lewy bodies in degenerating dopaminergic neurones in substantia nigra in idiopathic Parkinson's disease (PD) suggest that inhibition of normal/abnormal protein degradation may contribute to neuronal death. We now show for the first time that the chymotrypsin- (39%), trypsin- (42%) and postacidic-like (33%) hydrolysing activities of 20/26S proteasome are impaired in substantia nigra in PD. Proteasome inhibition does not appear to result from drug treatment since high concentrations of L-3,4-dihydroxyphenylalanine had no effect on enzymatic activity in vitro. These observations provide the first direct evidence that inhibition of the ubiquitin-proteasome pathway leading to altered protein handling and Lewy body formation may be responsible for degeneration of the nigrostriatal pathway in idiopathic PD.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylcysteine / analogs & derivatives*
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Acetylcysteine / pharmacology
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Aged
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Cysteine Endopeptidases / metabolism*
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Dihydroxyphenylalanine / pharmacology
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Enzyme Activation / drug effects
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Enzyme Inhibitors / pharmacology
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Female
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Humans
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Hydrolysis / drug effects
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Levodopa / metabolism
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Levodopa / pharmacology
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Lewy Bodies / metabolism
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Male
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Multienzyme Complexes / antagonists & inhibitors
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Multienzyme Complexes / metabolism*
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Parkinson Disease / metabolism*
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Parkinson Disease / pathology
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Peptide Hydrolases / metabolism*
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Proteasome Endopeptidase Complex
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Protein Processing, Post-Translational
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Substantia Nigra / enzymology*
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Substantia Nigra / pathology
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Ubiquitins / antagonists & inhibitors
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Ubiquitins / metabolism
Substances
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Enzyme Inhibitors
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Multienzyme Complexes
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Ubiquitins
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lactacystin
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Levodopa
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Dihydroxyphenylalanine
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Peptide Hydrolases
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Cysteine Endopeptidases
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Proteasome Endopeptidase Complex
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ATP dependent 26S protease
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Acetylcysteine