Does proteasome [corrected] inhibition decrease or accelerate toxin-induced dopaminergic neurodegeneration?
Parkinson's disease (PD) is pathologically characterized by dopaminergic (DA) cell death and the presence of Lewy bodies (LB) in the brain. alpha-Synuclein (alpha-syn) and ubiquitin (Ub) are the major components of LB, however, the process of their accumulation and their relationship to DA cell loss has not yet been resolved. Now, in this journal, Inden et al. showed the protective effect of proteasome inhibitors (PSI) on DA cell death in the rat PD model using 6-hydroxyl dopamine (6-OHDA). Co-administration of PSI, lactacystin, or MG-132 significantly prevented the nigral degeneration and apomorphine-induced rotational asymmetry of the model with increased appearance of alpha-syn- and Ub-positive inclusions in the substantia nigra. This study indicates that in their model, accelerated formation of inclusions via proteasome inhibition protects against DA cell death. Previous literature linked the impairments or inhibitions of the ubiquitin-proteasome system (UPS) and DA cell death. However, this report implies that the relationship between the UPS and the pathogenesis of PD may be more complex than we thought.
Setsuie
Rieko
R
Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo.
Kabuta
Tomohiro
T
Wada
Keiji
K
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D016631:Lewy Bodies / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009498:Neurotoxins / Q000494:pharmacology*; D016627:Oxidopamine / Q000494:pharmacology*; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D020011:Protective Agents / Q000378:metabolism*; D051381:Rats; D013378:Substantia Nigra / Q000473:pathology
D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D009498:Neurotoxins; D061988:Proteasome Inhibitors; D020011:Protective Agents; C067713:lactacystin; D016627:Oxidopamine; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D004298:Dopamine; D000111:Acetylcysteine