Proteasomal function is impaired in substantia nigra in Parkinson's disease.
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.
McNaught
K S
KS
Neurodegenerative Disease Research Centre, Division of Pharmacology and Therapeutics, Guy's, King's and St. Thomas' School of Biomedical Sciences, Hodgkin Building, King's College, Guy's Campus, SE1 1UL, London, UK.
Jenner
P
P
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000368:Aged; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004295:Dihydroxyphenylalanine / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D007980:Levodopa / Q000378:metabolism / Q000494:pharmacology; D016631:Lewy Bodies / Q000378:metabolism; D008297:Male; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D010447:Peptide Hydrolases / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D011499:Protein Processing, Post-Translational; D013378:Substantia Nigra / Q000201:enzymology* / Q000473:pathology; D014452:Ubiquitins / Q000037:antagonists & inhibitors / Q000378:metabolism
D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D014452:Ubiquitins; C067713:lactacystin; D007980:Levodopa; D004295:Dihydroxyphenylalanine; D010447:Peptide Hydrolases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D000111:Acetylcysteine