title: Proteasome inhibition leads to early loss of synaptic proteins in neuronal culture.
abstract: A dysfunctional ubiquitin proteasome system may be a mediating factor of disease progression in Lewy body dementia (LBD). The effects of proteasome inhibition using lactacystin and epoxomicin in primary neuronal culture were studied to assess the validity of this model to reflect the cortical pathology of LBD. Treatment of primary cortical neurons with 5 μM lactacystin for 24 h led to a 38 % reduction in the levels of β-III-tubulin (p < 0.05), a 48 % reduction in the levels of synaptophysin (p < 0.05) and a 74 % reduction in the levels of drebrin (p < 0.01), when compared to controls. Results for epoxomicin were similar. The loss of neuronal protein occurred prior to any loss of mitochondrial activity or cell death. The results are reflective of the loss of synapses and the synaptic changes observed in LBD, which may be an early event in the neurodegeneration of LBD. The similarities with the pathological changes in LBD highlight the possibility that this model can potentially provide a platform to test novel treatments.
authors.affiliation: Wolfson Centre for Age Related Diseases, Guy's Campus, King's College London, St. Thomas Street, London, SE1 1UL, UK.
authors.forename: Natasha
authors.initials: N
authors.lastname: Bajic
authors.forename: Peter
authors.initials: P
authors.lastname: Jenner
authors.forename: Clive G
authors.initials: CG
authors.lastname: Ballard
authors.forename: Paul T
authors.initials: PT
authors.lastname: Francis
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000633:toxicity; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000633:toxicity; D007150:Immunohistochemistry; D020961:Lewy Body Disease / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism; D009842:Oligopeptides / Q000633:toxicity; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*; D016708:Synaptophysin / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism; D054875:Ubiquitination; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D015853:Cysteine Proteinase Inhibitors; D009479:Neuropeptides; D009842:Oligopeptides; D016708:Synaptophysin; D014404:Tubulin; D051844:alpha-Synuclein; C053386:drebrins; C067713:lactacystin; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine; C078846:epoxomicin