Parkinson-like syndrome induced by continuous MPTP infusion: Convergent roles of the ubiquitin-proteasome system and α-synuclein

Francesco Fornai, Oliver M. Schlüter, Paola Lenzi, Marco Gesi, Riccardo Ruffoli, Michela Ferrucci, Gloria Lazzeri, Carla L. Busceti, Fabrizio Pontarelli, Giuseppe Battaglia, Antonio Pellegrini, Ferdinando Nicoletti, Stefano Ruggieri, Antonio Paparelli, Thomas C. Südhof

Research output: Contribution to journalArticlepeer-review

Abstract

In animals, sporadic injections of the mitochondrial toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) selectively damage dopaminergic neurons but do not fully reproduce the features of human Parkinson's disease. We have now developed a mouse Parkinson's disease model that is based on continuous MPTP administration with an osmotic minipump and mimics many features of the human disease. Although both sporadic and continuous MPTP administration led to severe striatal dopamine depletion and nigral cell loss, we find that only continuous administration of MPTP produced progressive behavioral changes and triggered formation of nigral inclusions immunoreactive for ubiquitin and α-synuclein. Moreover, only continuous MPTP infusions caused long-lasting activation of glucose uptake and inhibition of the ubiquitin-proteasome system. In mice lacking α-synuclein, continuous MPTP delivery still induced metabolic activation, but induction of behavioral symptoms and neuronal cell death were almost completely alleviated. Furthermore, the inhibition of the ubiquitin-proteasome system and the production of inclusion bodies were reduced. These data suggest that continuous low-level exposure of mice to MPTP causes a Parkinson-like syndrome in an α-synuclein-dependent manner.

Original languageEnglish
Pages (from-to)3413-3418
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number9
DOIs
Publication statusPublished - Mar 1 2005

Keywords

  • Lewy bodies
  • Mitochondria
  • Neurodegeneration
  • Neuronal inclusions

ASJC Scopus subject areas

  • Genetics
  • General

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