Proteasome inhibition and aggregation in Parkinson's disease

A comparative study in untransfected and transfected cells

Emiliano Biasini, Luana Fioriti, Ilaria Ceglia, Roberto Invernizzi, Alessandro Bertoli, Roberto Chiesa, Gianluigi Forloni

Research output: Contribution to journalArticle

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Abstract

Dysfunction of the ubiquitin-proteasome system (UPS) has been implicated in Parkinson's disease (PD) and other neurodegenerative disorders. We have investigated the effect of UPS inhibition on the metabolism of α-synuclein (SYN) and parkin, two proteins genetically and histopathologically associated to PD. Pharmacological inhibition of proteasome induced accumulation of both parkin and SYN in transfected PC12 cells. We found that this effect was caused by increased protein synthesis rather than impairment of protein degradation, suggesting that inhibition of the UPS might lead to non-specific up-regulation of cytomegalovirus (CMV)-driven transcription. To investigate whether endogenous parkin and SYN can be substrate of the UPS, untransfected PC12 cells and primary mesencephalic neurones were exposed to proteasome inhibitors, and parkin and SYN expression was evaluated at both protein and mRNA level. Under these conditions, we found that proteasome inhibitors did not affect the level of endogenous parkin and SYN. However, we confirmed that dopaminergic neurones were selectively vulnerable to the toxicity of proteasome inhibitors. Our results indicate that studies involving the use of proteasome inhibitors, particularly those in which proteins are expressed from a heterologous promoter, are subjected to potential artefacts that need to be considered for the interpretation of the role of UPS in PD pathogenesis.

Original languageEnglish
Pages (from-to)545-553
Number of pages9
JournalJournal of Neurochemistry
Volume88
Issue number3
DOIs
Publication statusPublished - Feb 2004

Fingerprint

Synucleins
Proteasome Endopeptidase Complex
Parkinson Disease
Ubiquitin
Proteasome Inhibitors
Agglomeration
PC12 Cells
Proteins
Neurons
Enzyme inhibition
Dopaminergic Neurons
Transcription
Cytomegalovirus
Metabolism
Neurodegenerative Diseases
Artifacts
Proteolysis
Toxicity
Up-Regulation
Pharmacology

Keywords

  • Mesencephalic cultures
  • Parkin
  • Parkinson's disease
  • Protein misfolding
  • Synuclein
  • Ubiquitin-proteasome

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Proteasome inhibition and aggregation in Parkinson's disease : A comparative study in untransfected and transfected cells. / Biasini, Emiliano; Fioriti, Luana; Ceglia, Ilaria; Invernizzi, Roberto; Bertoli, Alessandro; Chiesa, Roberto; Forloni, Gianluigi.

In: Journal of Neurochemistry, Vol. 88, No. 3, 02.2004, p. 545-553.

Research output: Contribution to journalArticle

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