title: Parkinson-like syndrome induced by continuous MPTP infusion: convergent roles of the ubiquitin-proteasome system and alpha-synuclein.
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 alpha-synuclein. Moreover, only continuous MPTP infusions caused long-lasting activation of glucose uptake and inhibition of the ubiquitin-proteasome system. In mice lacking alpha-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 ubiquitinproteasome 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 alpha-synuclein-dependent manner.
authors.affiliation: Department of Human Morphology and Applied Biology, University of Pisa, 56126 Pisa, Italy. f.fornai@med.unipi.it
authors.forename: Francesco
authors.initials: F
authors.lastname: Fornai
authors.forename: Oliver M
authors.initials: OM
authors.lastname: Schlüter
authors.forename: Paola
authors.initials: P
authors.lastname: Lenzi
authors.forename: Marco
authors.initials: M
authors.lastname: Gesi
authors.forename: Riccardo
authors.initials: R
authors.lastname: Ruffoli
authors.forename: Michela
authors.initials: M
authors.lastname: Ferrucci
authors.forename: Gloria
authors.initials: G
authors.lastname: Lazzeri
authors.forename: Carla L
authors.initials: CL
authors.lastname: Busceti
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Pontarelli
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Battaglia
authors.forename: Antonio
authors.initials: A
authors.lastname: Pellegrini
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
authors.forename: Stefano
authors.initials: S
authors.lastname: Ruggieri
authors.forename: Antonio
authors.initials: A
authors.lastname: Paparelli
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Südhof
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000008:administration & dosage*; D000818:Animals; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D020734:Parkinsonian Disorders / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D051843:Synucleins; D025801:Ubiquitin / Q000378:metabolism*; D051844:alpha-Synuclein
chemical_list: D009419:Nerve Tissue Proteins; C497605:Snca protein, mouse; D051843:Synucleins; D025801:Ubiquitin; D051844:alpha-Synuclein; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D046988:Proteasome Endopeptidase Complex
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