Proteasome inhibition causes nigral degeneration with inclusion bodies in rats.
Structural and functional defects in 26/20S proteasomes occur in the substantia nigra pars compacta and may underlie protein accumulation, Lewy body formation and dopaminergic neuronal death in Parkinson's disease. We therefore determined the pathogenicity of proteasomal impairment following stereotaxic unilateral infusion of lactacystin, a selective proteasome inhibitor, into the substantia nigra pars compacta of rats. These animals became progressively bradykinetic, adopted a stooped posture and displayed contralateral head tilting. Administration of apomorphine to lactacystin-treated rats reversed behavioral abnormalities and induced contralateral rotations. Lactacystin caused dose-dependent degeneration of dopaminergic cell bodies and processes with the cytoplasmic accumulation and aggregation of alpha-synuclein to form inclusion bodies. These findings support the notion that failure of the ubiquitin-proteasome system to degrade and clear unwanted proteins is an important etiopathogenic factor in Parkinson's disease.
McNaught
Kevin St P
KS
Department of Neurology, Mount Sinai School of Medicine, Annenberg 14-73, One Gustave L. Levy Place, New York, NY 10029, USA.
Björklund
Lars M
LM
Belizaire
Roger
R
Isacson
Ole
O
Jenner
Peter
P
Olanow
C Warren
CW
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D002479:Inclusion Bodies / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D010300:Parkinson Disease / Q000473:pathology; D010302:Parkinson Disease, Secondary / Q000139:chemically induced; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D017207:Rats, Sprague-Dawley; D020955:Striatonigral Degeneration / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology*; D013378:Substantia Nigra / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*
D009097:Multienzyme Complexes; C067713:lactacystin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D004298:Dopamine; D000111:Acetylcysteine