title: Manganese-induced toxicity in normal and human B lymphocyte cell lines containing a homozygous mutation in parkin.
abstract: Mutations in the parkin gene are linked to development of juvenile onset of Parkinson's disease and recent studies have reported that parkin can protect against increased oxidative stress and mitochondrial dysfunction caused by a variety of oxidative and toxic insults. Overexpression of parkin has also been reported to selectively protect dopaminergic neurons from Mn toxicity. Accordingly, in this paper we compare the effect that mutations in parkin have on Mn toxicity and associated apoptotic signals in normal and human B lymphocyte cell lines containing a homozygous mutation in the gene. Results of these studies reveal that Mn toxicity was similar in both control and mutant parkin lymphocyte cells indicating that cell death caused by Mn was not altered in cells devoid of parkin activity. In contrast, Mn did inhibit mitochondrial function to a greater extent in cells devoid of active parkin as indicated by a decrease in ATP production although mitochondrial membrane potential was essentially unaffected. Consistent with inactive parkin influencing the Mn response is the observation of increased activity in the down-stream apoptotic signal, caspase 3. In summary, results reported in this paper demonstrate that mutations in parkin can lead to functional changes in potential signaling processes known to provoke Mn toxicity. The selectivity and magnitude of this response, however, does not necessarily lead to cell death in lymphocytes which are devoid of dopamine.
authors: Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, NY 14214, USA. jaroth@buffalo.edu
authors: Jerome A
authors: JA
authors: Roth
authors: Balakrishnan
authors: B
authors: Ganapathy
authors: Andrew J
authors: AJ
authors: Ghio
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects; D002712:Chlorides / Q000633:toxicity*; D004298:Dopamine / Q000172:deficiency / Q000378:metabolism; D006801:Humans; D008297:Male; D017895:Manganese Compounds; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009154:Mutation; D015398:Signal Transduction / Q000187:drug effects; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
chemical_list: D002712:Chlorides; D017895:Manganese Compounds; D000255:Adenosine Triphosphate; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D053148:Caspase 3; C025340:manganese chloride; D004298:Dopamine