Dataset Information

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.

SUBMITTER: Fornai F

PROVIDER: S-EPMC552938 | biostudies-literature | 2005 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Parkinson-like syndrome induced by continuous MPTP infusion: convergent roles of the ubiquitin-proteasome system and alpha-synuclein.

Fornai Francesco F Schlüter Oliver M OM Lenzi Paola P Gesi Marco M Ruffoli Riccardo R Ferrucci Michela M Lazzeri Gloria G Busceti Carla L CL Pontarelli Fabrizio F Battaglia Giuseppe G Pellegrini Antonio A Nicoletti Ferdinando F Nicoletti Ferdinando F Ruggieri Stefano S Paparelli Antonio A Südhof Thomas C TC

Proceedings of the National Academy of Sciences of the United States of America 20050216 9

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 ...[more]

PMID: 15716361

Similar Datasets

Project description:BackgroundThe accumulation of α-synuclein (α-syn), an essential step in PD development and progression, is observed not only in neurons but also in glia, including astrocytes. The mechanisms regulating astrocytic α-syn level and aggregation remain unclear. More recently, it has been demonstrated that a part of α-syn spreading occurs through extracellular vesicles (EVs), although it is unknown whether this process is involved in astrocytes of PD. It is known, however, that EVs derived from the central nervous system exist in the blood and are extensively explored as biomarkers for PD and other neurodegenerative disorders.MethodsPrimary astrocytes were transfected with A53T α-syn plasmid or exposed to α-syn aggregates. The level of astrocyte-derived EVs (AEVs) was assessed by nanoparticle tracking analysis and immunofluorescence. The lysosomal function was evaluated by Cathepsin assays, immunofluorescence for levels of Lamp1 and Lamp2, and LysoTracker Red staining. The Apogee assays were optimized to measure the GLT-1+ AEVs in clinical cohorts of 106 PD, 47 multiple system atrophy (MSA), and 103 healthy control (HC) to test the potential of plasma AEVs as a biomarker to differentiate PD from other forms of parkinsonism.ResultsThe number of AEVs significantly increased in primary astrocytes with α-syn deposition. The mechanism of increased AEVs was partially attributed to lysosomal dysfunction. The number of α-syn-carrying AEVs was significantly higher in patients with PD than in HC and MSA. The integrative model combining AEVs with total and aggregated α-syn exhibited efficient diagnostic power in differentiating PD from HC with an AUC of 0.915, and from MSA with an AUC of 0.877.ConclusionsPathological α-syn deposition could increase the astrocytic secretion of EVs, possibly through α-syn-induced lysosomal dysfunction. The α-syn-containing AEVs in the peripheral blood may be an effective biomarker for clinical diagnosis or differential diagnosis of PD.

Dataset Information

Parkinson-like syndrome induced by continuous MPTP infusion: convergent roles of the ubiquitin-proteasome system and alpha-synuclein.

Publications

Parkinson-like syndrome induced by continuous MPTP infusion: convergent roles of the ubiquitin-proteasome system and alpha-synuclein.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets