Convergent roles of α-synuclein, DA metabolism, and the ubiquitin-proteasome system in nigrostriatal toxicity

Francesco Fornai, Gloria Lazzeri, Adolfo Bandettini Di Poggio, Paola Soldani, Antonio De Blasi, Ferdinando Nicoletti, Stefano Ruggieri, Antonio Paparelli

Research output: Chapter in Book/Report/Conference proceedingConference contribution

Abstract

Recent studies disclosed the relevance of specific molecules for the onset of Parkinson's disease (PD) and for the composition of neuronal inclusions. The scenario which is now emerging leads to identify a potential common pathway named the ubiquitin-proteasome (UP) system. In line with this, striatal or systemic inhibiton of the UP system causes experimental Parkinsonism characterized by the formation of neuronal inclusions. 1-Methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP), which is also a complex I inhibitor, has been used for decades to produce experimental Parkinsonism with no evidence for neuronal inclusions in rodents. This leaves open the question whether neuronal inclusions need an alternative mechanism or the inhibition of complex I needs to be carried out continuously to build up inclusions. In the present article, we administered continuously MPTP. In these experimental conditions we compared the neurological consequence of intermittent versus continuous MPTP. In both cases we observed a severe dopamine (DA) denervation and cell loss. However, when MPTP was delivered continuously, spared DA nigral neurons develop ubiquitin, parkin, and α-synuclein positive inclusions, which are not detectable after intermittent dosing. The onset of Parkinsonism is associated with inhibition of the UP system. We compared these results with those obtained with amphetamine derivative in vivo and in vitro in which occurrence of neuronal inclusions was associated with inhibition of the UP system and we evaluated the role of DA metabolism in inducing these effects.

Original languageEnglish
Title of host publicationAnnals of the New York Academy of Sciences
Pages84-89
Number of pages6
Volume1074
DOIs
Publication statusPublished - Aug 2006

Publication series

NameAnnals of the New York Academy of Sciences
Volume1074
ISSN (Print)00778923
ISSN (Electronic)17496632

Keywords

  • Methamphetamine (METH)
  • Neurodegeneration
  • Parkin-levels
  • Parkinsonism
  • Striatum nervous systems

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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