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Neurobiol Aging. 2011 Nov;32(11):2100-2. doi: 10.1016/j.neurobiolaging.2009.11.015. Epub 2009 Dec 16.

Chronic systemic treatment with a high-dose proteasome inhibitor in mice produces akinesia unrelated to nigrostriatal degeneration.

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Commissariat à l'Energie Atomique (CEA), Institut d'Imagerie Biomédicale (I(2)BM), Molecular Imaging Research Center (MIRCen), Bat 61, 18 route du Panorama, BP n°6, F-92265 Fontenay-aux-Roses, France.


Supporting the hypothesis that proteasome dysfunction is involved in Parkinson's disease (PD), McNaught et al. (2004) reported that the systemic administration of the proteasome inhibitor Z-Ile-Glu(OtBu)-Ala-Leu-aldehyde (PSI) in rats led to the degeneration of the nigrostriatal pathway. However, several groups could not reproduce this finding. We herein attempted to improve the reliability of the PSI model by chronically delivering the inhibitor using osmotic minipumps in aged mice. We also tested whether PSI co-administered with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) could act synergistically to induce toxicity. We found that PSI produced a significant reduction in locomotor activity that was mildly exacerbated by MPTP. However, PSI alone produced no sign of degeneration of the nigrostriatal dopaminergic pathway and did not exacerbate MPTP toxicity. To conclude, PSI administration does not provide a reliable phenotypic model of PD.

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