Journal of Neural Transmission

, Volume 115, Issue 6, pp 869–878 | Cite as

Proteasomal abnormalities in cortical Lewy body disease and the impact of proteasomal inhibition within cortical and cholinergic systems

  • Nicholas MacInnes
  • Mahmoud M. Iravani
  • Elaine Perry
  • Margaret Piggott
  • Robert Perry
  • Peter Jenner
  • Clive Ballard
Alzheimer's Disease and Related Disorders - Original Article

Abstract

Dementia with Lewy bodies (DLB) accounts for 15–20% of the millions of people worldwide with dementia. In the current work we investigate the association between proteasome dysfunction and the development of cortical Lewy body pathology. Analysis of post-mortem cortical tissue indicated levels of the α-subunit of the 20S proteasome were significantly reduced in DLB cortex, but not Alzheimer’s, in comparison to control and this reduction correlated with both the severity and duration of dementia. Application of proteasome inhibitors to rodent cortical primary neurones in vitro and by direct injection onto rodent cholinergic forebrain neurons in vivo gave rise to dose dependent neuronal death and in rodent cortex––marked cholinergic deficits accompanied by the accumulation of inclusions that stained positive for α-synuclein and ubiquitin. These findings suggest that proteasomal abnormalities are present within cortical Lewy body disease and the experimental inhibition of proteasomal function mirrors the neuropathological changes seen within the disorder.

Keywords

Dementia with Lewy bodies Ubiquitin-proteasome system Nucleus basalis magnocellularis Lactacystin α-Synuclein Ubiquitin 

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Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Nicholas MacInnes
    • 1
  • Mahmoud M. Iravani
    • 2
  • Elaine Perry
    • 3
  • Margaret Piggott
    • 3
  • Robert Perry
    • 3
  • Peter Jenner
    • 2
  • Clive Ballard
    • 1
  1. 1.Wolfson Centre for Age-Related DiseaseKing’s College LondonLondonUK
  2. 2.Neurodegenerative Disease Research GroupKing’s College LondonLondonUK
  3. 3.Institute for Ageing and HealthUniversity of Newcastle upon Tyne, Newcastle General HospitalNewcastle upon TyneUK

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