Dataset Information

Calcineurin determines toxic versus beneficial responses to ?-synuclein.

ABSTRACT: Calcineurin (CN) is a highly conserved Ca(2+)-calmodulin (CaM)-dependent phosphatase that senses Ca(2+) concentrations and transduces that information into cellular responses. Ca(2+) homeostasis is disrupted by ?-synuclein (?-syn), a small lipid binding protein whose misfolding and accumulation is a pathological hallmark of several neurodegenerative diseases. We report that ?-syn, from yeast to neurons, leads to sustained highly elevated levels of cytoplasmic Ca(2+), thereby activating a CaM-CN cascade that engages substrates that result in toxicity. Surprisingly, complete inhibition of CN also results in toxicity. Limiting the availability of CaM shifts CN's spectrum of substrates toward protective pathways. Modulating CN or CN's substrates with highly selective genetic and pharmacological tools (FK506) does the same. FK506 crosses the blood brain barrier, is well tolerated in humans, and is active in neurons and glia. Thus, a tunable response to CN, which has been conserved for a billion years, can be targeted to rebalance the phosphatase's activities from toxic toward beneficial substrates. These findings have immediate therapeutic implications for synucleinopathies.

SUBMITTER: Caraveo G

PROVIDER: S-EPMC4151770 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Calcineurin determines toxic versus beneficial responses to α-synuclein.

Caraveo Gabriela G Auluck Pavan K PK Whitesell Luke L Chung Chee Yeun CY Baru Valeriya V Mosharov Eugene V EV Yan Xiaohui X Ben-Johny Manu M Soste Martin M Picotti Paola P Kim Hanna H Caldwell Kim A KA Caldwell Guy A GA Sulzer David D Yue David T DT Lindquist Susan S

Proceedings of the National Academy of Sciences of the United States of America 20140813 34

Calcineurin (CN) is a highly conserved Ca(2+)-calmodulin (CaM)-dependent phosphatase that senses Ca(2+) concentrations and transduces that information into cellular responses. Ca(2+) homeostasis is disrupted by α-synuclein (α-syn), a small lipid binding protein whose misfolding and accumulation is a pathological hallmark of several neurodegenerative diseases. We report that α-syn, from yeast to neurons, leads to sustained highly elevated levels of cytoplasmic Ca(2+), thereby activating a CaM-CN ...[more]

PMID: 25122673

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Project description:Manganese (Mn) is an essential trace element, which also causes neurotoxicity in exposed occupational workers. Mn causes mitochondrial toxicity; however, little is known about transcriptional responses discriminated by physiological and toxicological levels of Mn. Identification of such mechanisms could provide means to evaluate risk of Mn toxicity and also potential avenues to protect against adverse effects. To study the Mn dose-response effects on transcription, analyzed by RNA-Seq, we used human SH-SY5Y neuroblastoma cells exposed for 5 h to Mn (0 to 100 ?M), a time point where no immediate cell death occurred at any of the doses. Results showed widespread effects on abundance of protein-coding genes for metabolism of reactive oxygen species, energy sensing, glycolysis, and protein homeostasis including the unfolded protein response and transcriptional regulation. Exposure to a concentration (10 ?M Mn for 5 h) that did not result in cell death after 24-h increased abundance of differentially expressed genes (DEGs) in the protein secretion pathway that function in protein trafficking and cellular homeostasis. These include BET1 (Golgi vesicular membrane-trafficking protein), ADAM10 (ADAM metallopeptidase domain 10), and ARFGAP3 (ADP-ribosylation factor GTPase-activating protein 3). In contrast, 5-h exposure to 100 ?M Mn, a concentration that caused cell death after 24 h, increased abundance of DEGs for components of the mitochondrial oxidative phosphorylation pathway. Integrated pathway analysis results showed that protein secretion gene set was associated with amino acid metabolites in response to 10 ?M Mn, while oxidative phosphorylation gene set was associated with energy, lipid, and neurotransmitter metabolites at 100 ?M Mn. These results show that differential effects of Mn occur at a concentration which does not cause subsequent cell death compared to a concentration that causes subsequent cell death. If these responses translate to effects on the secretory pathway and mitochondrial functions in vivo, differential activities of these systems could provide a sensitive basis to discriminate sub-toxic and toxic environmental and occupational Mn exposures.

Dataset Information

Calcineurin determines toxic versus beneficial responses to ?-synuclein.

Publications

Calcineurin determines toxic versus beneficial responses to α-synuclein.

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