期刊
FEBS JOURNAL
卷 276, 期 18, 页码 5041-5052出版社
WILEY
DOI: 10.1111/j.1742-4658.2009.07201.x
关键词
autosomal recessive juvenile Parkinsonism; calcium; parkin; Parkinson's disease; phospholipase C
资金
- Swedish foundations
- Swedish Brain Power
- Parkinsonsfonden
- Riskbankens Jubileum Fond
- Karolinska Institutets Foundation for Geriatric Research
- Loo and Hans Ostermans Foundation
- Gun and Bertil Stohnes Foundation
- K. A. Wallenberg
- Stiftelsen for Gamla Tjanarinnor and Ake Wibergs Foundation
- Intramural Research Program of the National Institute on Aging
- National Institutes of Health
- Ayudas Postdoctorales
- Gobierno de Navarra and LIONS Foundation for Research of Age Related Disorders
- NATIONAL INSTITUTE ON AGING [ZIAAG000938] Funding Source: NIH RePORTER
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 C gamma 1 is a substrate for parkin. In this article, we show that parkin mutants and siRNA parkin knockdown cells possess enhanced levels of phospholipase C gamma 1 phosphorylation, basal phosphoinositide hydrolysis and intracellular Ca2+ concentration. The protein levels of Ca2+-regulated protein kinase C alpha were decreased in AJRP parkin mutant cells. Neomycin and dantrolene both decreased the intracellular Ca2+ 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 Ca2+ release from ryanodine-sensitive stores decreases the toxic effects of 6OHDA. Our findings suggest that parkin is an important factor for maintaining Ca2+ homeostasis and that parkin deficiency leads to a phospholipase C-dependent increase in intracellular Ca2+ levels, which make cells more vulnerable to neurotoxins, such as 6OHDA.
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