title: Proteasomal inhibition causes loss of nigral tyrosine hydroxylase neurons.
abstract: Dysfunction of the ubiquitin-proteasomal system (UPS) has been implicated in the pathogenesis of Parkinson's disease. The systemic administration of UPS inhibitors has been reported to induce nigrostriatal cell death and model Parkinson's disease pathology in rodents. We administered a synthetic, specific UPS inhibitor (PSI) subcutaneously to rats and quantified substantia nigral tyrosine hydroxylase-positive dopaminergic neurons by stereology. PSI caused a 15% decrease in UPS activity at 2 weeks and a 42% reduction in substantia nigra pars compacta tyrosine hydroxylase-positive neurons at 8 weeks. Systemic inhibition of the UPS warrants further evaluation as a means to model Parkinson's disease.
authors.affiliation: University Department of Clinical Neurosciences, Royal Free and University College, Medical School, London, United Kingdom. schapira@medsch.ucl.ac.uk
authors.forename: Anthony H V
authors.initials: AH
authors.lastname: Schapira
authors.forename: Michael W J
authors.initials: MW
authors.lastname: Cleeter
authors.forename: John R
authors.initials: JR
authors.lastname: Muddle
authors.forename: Jane M
authors.initials: JM
authors.lastname: Workman
authors.forename: J Mark
authors.initials: JM
authors.lastname: Cooper
authors.forename: Rosalind H M
authors.initials: RH
authors.lastname: King
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D002918:Chymotrypsin / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D006120:Grooming / Q000187:drug effects; D018737:Hand Strength; D009043:Motor Activity / Q000187:drug effects; D009129:Muscle Tonus / Q000187:drug effects; D009474:Neurons / Q000201:enzymology*; D009842:Oligopeptides / Q000494:pharmacology*; D004856:Postural Balance / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012018:Reflex / Q000187:drug effects; D013378:Substantia Nigra / Q000166:cytology* / Q000201:enzymology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*; D015430:Weight Gain / Q000187:drug effects
chemical_list: D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; C090535:benzyloxycarbonyl-isoleucyl-glutamyl(O-tert-butyl)-alanyl-leucinal; D014446:Tyrosine 3-Monooxygenase; D002918:Chymotrypsin; D046988:Proteasome Endopeptidase Complex