Proteasome inhibition causes nigral degeneration with inclusion bodies in rats

Kevin St P. McNaught, Lars M. Björklund, Roger Belizaire, Ole Isacson, Peter Jenner, C. Warren Olanow

Research output: Contribution to journalArticlepeer-review

240 Scopus citations

Abstract

Structural and functional defects in 26/20S proteasomes occur in the substantia nigra pars compacta and may underlie protein accumulation, Lewy body formation and dopaminergic neuronal death in Parkinson's disease. We therefore determined the pathogenicity of proteasomal impairment following stereotaxic unilateral infusion of lactacystin, a selective proteasome inhibitor, into the substantia nigra pars compacta of rats. These animals became progressively bradykinetic, adopted a stooped posture and displayed contralateral head tilting. Administration of apomorphine to lactacystin-treated rats reversed behavioral abnormalities and induced contralateral rotations. Lactacystin caused dose-dependent degeneration of dopaminergic cell bodies and processes with the cytoplasmic accumulation and aggregation of α-synuclein to form inclusion bodies. These findings support the notion that failure of the ubiquitin-proteasome system to degrade and clear unwanted proteins is an important etiopathogenic factor in Parkinson's disease.

Original languageEnglish
Pages (from-to)1437-1441
Number of pages5
JournalNeuroReport
Volume13
Issue number11
DOIs
StatePublished - 7 Aug 2002

Keywords

  • Lactacystin
  • Lewy body inclusion
  • Parkin
  • Parkinson's disease
  • Substantia nigra pars compacta
  • Ubiquitin-proteasome system
  • α-Synuclein

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