| Title | Parkin deficiency disrupts calcium homeostasis by modulating phospholipase C signalling. | | Author(s) | Sandebring A, Dehvari N, Perez-Manso M, Thomas KJ, Karpilovski E, Cookson MR, Cowburn RF, Cedazo-Mínguez A | | Institution | Karolinska Institutet, Department of NVS, KI-Alzheimer's Disease Research Center, Stockholm, Sweden. | | Source | FEBS J 2009 Aug 3. | | Abstract | Mutations in the E3 ubiquitin ligase parkin cause early-onset, autosomal-recessive juvenile parkinsonism (AJRP), presumably as a result of a lack of function that alters the level, activity, aggregation or localization of its substrates. Recently, we have reported that phospholipase Cgamma1 is a substrate for parkin. In this article, we show that parkin mutants and siRNA parkin knockdown cells possess enhanced levels of phospholipase Cgamma1 phosphorylation, basal phosphoinositide hydrolysis and intracellular Ca(2+) concentration. The protein levels of Ca(2+)-regulated protein kinase Calpha were decreased in AJRP parkin mutant cells. Neomycin and dantrolene both decreased the intracellular Ca(2+) levels in parkin mutants in comparison with those seen in wild-type parkin cells, suggesting that the differences were a consequence of altered phospholipase C activity. The protection of wild-type parkin against 6-hydroxydopamine (6OHDA) toxicity was also established in ARJP mutants on pretreatment with dantrolene, implying that a balancing Ca(2+) release from ryanodine-sensitive stores decreases the toxic effects of 6OHDA. Our findings suggest that parkin is an important factor for maintaining Ca(2+) homeostasis and that parkin deficiency leads to a phospholipase C-dependent increase in intracellular Ca(2+) levels, which make cells more vulnerable to neurotoxins, such as 6OHDA. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19663908 |
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