title: Effect of divalent metals on the neuronal proteasomal system, prion protein ubiquitination and aggregation.
abstract: The role of normal cellular prion protein (PrP) remains to be fully elucidated; however, the protein is crucial for the infection and progression of prion diseases. Recent evidence indicates that PrP is a metalloprotein since the octapeptide repeat sequences in the protein have high affinity for various divalent cations and the binding sites appear to play a role in the pathogenesis of prion diseases. In our present study, we tested several divalent metals including manganese and cadmium and determined their effects on protein degradation and protein aggregation in mouse neuronal cells expressing PrP. Cadmium was more neurotoxic than manganese following 24h exposure. Manganese did not show any significant effect on the inhibition of proteasomal activity or formation of high molecular weight ubiquitinated PrPs. Interestingly, treatment with cadmium profoundly inhibited proteasomal activity, which resulted in greatly increased formation of high molecular weight ubiquitinated PrPs. Immunohistochemical analysis also revealed a dramatic increase in formation of oligomers after cadmium treatment. Cadmium also increased the formation of ubiquitinated PrP, but it did not lead to the formation of proteinase-K resistant PrP. Collectively, our results show that a divalent metal, cadmium affects proteasomal function and PrP aggregation, which promote neurotoxicity.
authors.affiliation: Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, IA 50011, USA. akanthas@iastate.edu
authors.forename: A G
authors.initials: AG
authors.lastname: Kanthasamy
authors.forename: C
authors.initials: C
authors.lastname: Choi
authors.forename: H
authors.initials: H
authors.lastname: Jin
authors.forename: D S
authors.initials: DS
authors.lastname: Harischandra
authors.forename: V
authors.initials: V
authors.lastname: Anantharam
authors.forename: A
authors.initials: A
authors.lastname: Kanthasamy
mesh_terms: D000818:Animals; D019256:Cadmium Chloride / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002712:Chlorides / Q000009:adverse effects*; D017895:Manganese Compounds / Q000009:adverse effects*; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011328:Prions / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects* / Q000378:metabolism; D055503:Protein Multimerization / Q000187:drug effects*; D054875:Ubiquitination / Q000187:drug effects*
chemical_list: D002712:Chlorides; D017895:Manganese Compounds; D011328:Prions; D046988:Proteasome Endopeptidase Complex; D019256:Cadmium Chloride; C025340:manganese chloride