Proteasomal abnormalities in cortical Lewy body disease and the impact of proteasomal inhibition within cortical and cholinergic systems.
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.
MacInnes
Nicholas
N
Wolfson Centre for Age-Related Disease, King's College London, London, UK. nicholas.macinnes@kcl.ac.uk
Iravani
Mahmoud M
MM
Perry
Elaine
E
Piggott
Margaret
M
Perry
Robert
R
Jenner
Peter
P
Ballard
Clive
C
D000109:Acetylcholine / Q000378:metabolism; D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000633:toxicity; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D020532:Basal Nucleus of Meynert / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002799:Cholinergic Fibers / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005260:Female; D006801:Humans; D016631:Lewy Bodies / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020961:Lewy Body Disease / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009842:Oligopeptides / Q000633:toxicity; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D025801:Ubiquitin / Q000187:drug effects / Q000378:metabolism; D051844:alpha-Synuclein / Q000187:drug effects / Q000378:metabolism
D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D009842:Oligopeptides; D061988:Proteasome Inhibitors; D025801:Ubiquitin; D051844:alpha-Synuclein; C067713:lactacystin; D046988:Proteasome Endopeptidase Complex; D000109:Acetylcholine; D000111:Acetylcysteine; C078846:epoxomicin