Targeted disruption of neuronal 19S proteasome subunits induces the formation of ubiquitinated inclusions in the absence of cell death

Anna Droggiti, Cherry Chen Ying Ho, Leonidas Stefanis, William T. Dauer, Hardy J. Rideout

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Proteasome-mediated proteolysis is a major protein degradation mechanism in cells and its dysfunction has been implicated in the pathogenesis of several neurodegenerative diseases, each with the common features of neuronal death and formation of ubiquitinated inclusions found within neurites, the cell body, or nucleus. Previous models of proteasome dysfunction have employed pharmacological inhibition of the catalytic subunits of the 20S proteasome core, or the genetic manipulation of specific subunits resulting in altered proteasome assembly. In this study, we report the use of dominant negative subunits of the 19S regulatory proteasome complex that mediate the recognition of ubiquitinated substrates as well as the removal of the poly-ubiquitin chain. Interestingly, while each mutant subunit-induced inclusion formation, like that seen with pharmacological inhibition of the 20S proteasome, none was able to induce apoptotic death, or trigger activation of macroautophagy, in either dopaminergic cell lines or primary cortical neurons. This finding highlights the dissociation between the mechanisms of neuronal inclusion formation and the induction of cell death, and represents a novel cellular model for Lewy body-like inclusion formation in neurons.

Original languageEnglish (US)
Pages (from-to)630-643
Number of pages14
JournalJournal of Neurochemistry
Volume119
Issue number3
DOIs
StatePublished - Nov 1 2011
Externally publishedYes

Fingerprint

Cell death
Proteasome Endopeptidase Complex
Cell Death
Proteolysis
Neurons
Cells
Polyubiquitin
Pharmacology
Neurodegenerative diseases
Lewy Bodies
Autophagy
Neurites
Cell Nucleus
Neurodegenerative Diseases
Catalytic Domain
Chemical activation
Cell Line
Degradation
Substrates
Proteins

Keywords

  • α-synuclein
  • 19S
  • inclusion
  • neuron
  • proteasome
  • ubiquitin

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Targeted disruption of neuronal 19S proteasome subunits induces the formation of ubiquitinated inclusions in the absence of cell death. / Droggiti, Anna; Ho, Cherry Chen Ying; Stefanis, Leonidas; Dauer, William T.; Rideout, Hardy J.

In: Journal of Neurochemistry, Vol. 119, No. 3, 01.11.2011, p. 630-643.

Research output: Contribution to journalArticle

Droggiti, Anna ; Ho, Cherry Chen Ying ; Stefanis, Leonidas ; Dauer, William T. ; Rideout, Hardy J. / Targeted disruption of neuronal 19S proteasome subunits induces the formation of ubiquitinated inclusions in the absence of cell death. In: Journal of Neurochemistry. 2011 ; Vol. 119, No. 3. pp. 630-643.
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