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

Journal of Neural Transmission
Nicholas MacInnesClive Ballard

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 alpha-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 alpha-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.

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Citations

Jun 30, 2012·Acta Neuropathologica·Darius Ebrahimi-FakhariPamela J McLean
Sep 4, 2009·Journal of Neurology·Kurt A Jellinger
May 18, 2012·Journal of Neural Transmission·Natasha BajicPaul T Francis
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Oct 6, 2011·Drugs & Aging·Clive BallardAnne Corbett
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May 12, 2018·Neuropathology : Official Journal of the Japanese Society of Neuropathology·Rowan GurneyDavid M A Mann
Nov 8, 2008·Current Opinion in Neurology

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