Systemic exposure to proteasome inhibitors causes a progressive model of Parkinson's disease.
Environmental toxins have been implicated in the etiology of Parkinson's disease. Recent findings of defects in the ubiquitin-proteasome system in hereditary and sporadic forms of the illness suggest that environmental proteasome inhibitors are candidate PD-inducing toxins. Here, we systemically injected six doses of naturally occurring (epoxomicin) or synthetic (Z-lle-Glu(OtBu)-Ala-Leu-al [PSI]) proteasome inhibitors into adult rats over a period of 2 weeks. After a latency of 1 to 2 weeks, animals developed progressive parkinsonism with bradykinesia, rigidity, tremor, and an abnormal posture, which improved with apomorphine treatment. Positron emission tomography demonstrated reduced carbon-11-labeled 2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane (CFT) binding to dopaminergic nerve terminals in the striatum, indicative of degeneration of the nigrostriatal pathway. Postmortem analyses showed striatal dopamine depletion and dopaminergic cell death with apoptosis and inflammation in the substantia nigra pars compacta. In addition, neurodegeneration occurred in the locus coeruleus, dorsal motor nucleus of the vagus, and the nucleus basalis of Meynert. At neurodegenerative sites, intracytoplasmic, eosinophilic, alpha-synuclein/ubiquitin-containing, inclusions resembling Lewy bodies were present in some of the remaining neurons. This animal model induced by proteasome inhibitors closely recapitulates key features of PD and may be valuable in studying etiopathogenic mechanisms and putative neuroprotective therapies for the illness.
McNaught
Kevin St  P
KS
Department of Neurology, Neuropathology Division, Mount Sinai School of Medicine, New York, NY 10029, USA. kevin.mcnaught@mssm.edu
Perl
Daniel P
DP
Brownell
Anna-Liisa
AL
Olanow
C Warren
CW
D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use; D001058:Apomorphine / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D002250:Carbon Radioisotopes / Q000378:metabolism; D003042:Cocaine / Q000031:analogs & derivatives* / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity*; D018765:Dopamine Uptake Inhibitors / Q000378:metabolism; D015386:Hazardous Substances / Q000494:pharmacology / Q000633:toxicity*; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism; D008297:Male; D015394:Molecular Structure; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced* / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D017207:Rats, Sprague-Dawley; D014055:Tomography, Emission-Computed
D000978:Antiparkinson Agents; D002250:Carbon Radioisotopes; D015853:Cysteine Proteinase Inhibitors; D018765:Dopamine Uptake Inhibitors; D015386:Hazardous Substances; D009097:Multienzyme Complexes; D009842:Oligopeptides; C090535:benzyloxycarbonyl-isoleucyl-glutamyl(O-tert-butyl)-alanyl-leucinal; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D003042:Cocaine; D001058:Apomorphine; C078846:epoxomicin