Lack of nigrostriatal pathology in a rat model of proteasome inhibition

Abstract

Systemic administration of ubiquitin-proteasome system inhibitors to rodents has been reported to induce certain behavioral and neuropathological features of Parkinson's disease. The goal of this study was to replicate these observations by administering a proteasome inhibitor (PSI) to rats using McNaught and colleagues' protocol. No alterations in locomotor activity or striatal dopamine and its metabolites were observed. Differences in nigral dopaminergic cell number between proteasome inhibitor- and vehicle-treated rats and inclusion bodies were not found. Extending the time of survival after administration and using different solvents failed to alter results, indicating this proteasome inhibitor does not consistently produce the selective toxicity and pathological hallmarks characterizing Parkinson's disease.

Original article Nigrostriatal pathway degeneration in rats after intraperitoneal administration of proteasome inhibitor MG-132

“…In some experimental conditions, mainly after subcutaneous administration of PSI, a loss of SN dopaminergic neurons was observed and varied between 40% [38] and 50% [51], and even exceeded 50% [33]. Four other groups of researchers, despite the fact that they tried faithfully to follow the experimental protocol proposed by McNaught et al, failed to replicate the results described earlier [6,22,23,30]. Our results support the theory of McNaught et al…”

A Novel “Molecular Tweezer” Inhibitor of α-Synuclein Neurotoxicity in Vitro and in Vivo

“…Two known genetic causes of PD involve aspects of UPS function (Parkin and UCH-L1), and α-syn is a substrate for the UPS. Reduced UPS activity has been found in brains of sporadic PD patients [48,49] and some investigators have found that administration of UPS inhibitors to rodents can recreate some of the features of PD, although these models remain controversial [50][51][52][53][54][55]. Finally, we have found that several commonly used pesticides inhibit the UPS and are associated with an increased risk of developing PD [7,13].…”

Systemic administration of a proteasome inhibitor does not cause nigrostriatal dopamine degeneration

“…Moreover, decreased locomotor activity was reported to occur in response to PSI treatment. However, since this report three other papers have failed to replicate various aspects of the original findings (Bove et al, 2006;Kordower et al, 2006;Manning-Bog et al, 2006), while two other papers have replicated aspects of the orginal report (Schapira et al, 2006;Zeng et al, 2006).…”