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Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder characterized by loss of motor neurons. Dominant mutations in the gene for superoxide dismutase 1 (SOD1) give rise to familial ALS by an unknown mechanism. Here we show that genetic deficiency of mammalian sterile 20-like kinase 1 (MST1) delays disease onset and extends survival in mice expressing the ALS-associated G93A mutant of human SOD1. SOD1(G93A) induces dissociation of MST1 from a redox protein thioredoxin-1 and promotes MST1 activation in spinal cord neurons in a reactive oxygen species-dependent manner. Moreover, MST1 was found to mediate SOD1 (G93A)-induced activation of p38 mitogen-activated protein kinase and caspases as well as impairment of autophagy in spinal cord motoneurons of SOD1(G93A) mice. Our findings implicate MST1 as a key determinant of neurodegeneration in ALS. [ABSTRACT FROM AUTHOR]

Endogenous opioids generate analgesic signals in the periaqueductal gray (PAG). However, because cell types in the PAG are difficult to identify, its neuronal mechanism has remained poorly understood. To address this issue, we characterized PAG neurons by their electrical properties using differentially labeled GABAer-gic and output neurons in the PAG. We found that GABAergic neurons were mostly fast-spiking cells and could be further divided into two distinct classes: with or without low-threshold spikes (LTS) driven by T-type channels. In contrast, the PAG output neurons lacked ITS and showed heterogeneous firing patterns. To reveal the function of the LTS, we examined the mutant mice lacking the alG T-type channels (ulG'i. The mutant mice lacked LTS in the fast-spiking GABAergic neurons of the PAG and unex- pectedly showed impaired opioid-dependent analgesia; a similar phenotype was reproduced in PAG-specific alG-knockdown mice. Electrophysiological analyses revealed functional expression of popioid receptors in the low threshold-spiking GABAergic neurons. These neurons in the mutant lacking LTS showed markedly enhanced discharge activities, which led to an augmented inhibition of output neurons. Furthermore, the impaired analgesia observed in alG' mice was reversed by blocking local GABAA receptors. These results indicate that aiG T-type channels are critical for the opioidergic descending analgesia system in the PAG. [ABSTRACT FROM AUTHOR]

Calcium and integrin binding protein 1 (CIB1) is a Ca2+-binding protein of 22 kDa that was initially identified as a protein that interacts with integrin αIIb. Although it interacts with various proteins and has been implicated in diverse cellular functions, the molecular mechanism by which CIB1 regulates intracellular signaling networks has remained unclear. We now show that, by targeting apoptosis signal-regulating kinase 1 (ASK1), CIB1 negatively regulates stress-activated MAPK signaling pathways. CIB1 was thus shown to bind to ASK1, to interfere with the recruitment of TRAF2 to ASK1, and to inhibit the autophosphorylation of ASK1 on threonine-838, thereby blocking ASK1 activation. Furthermore, CIB1 mitigated apoptotic cell death initiated either by TNF-α in breast cancer MCF7 cells or by 6-hydroxydopamine (6-OHDA) in dopaminergic cells. Ca2+ influx induced by membrane depolarization reversed the inhibitory effect of CIB1 on 6-OHDA-induced ASK1 activation and cell death in dopaminergic neurons. These observations thus suggest that CIB1 functions as a Ca2+-sensitive negative regulator of ASK1-mediated signaling events. [ABSTRACT FROM AUTHOR]

The transmembrane protein Notch is cleaved by γ-secretase to yield an active form, Notch intracellular domain (Notch-IC), in response to the binding of ligands. such as Jagged. Notch-IC contributes to the regulation of a variety of cellular events, including cell fate determination during embryonic development as well as cell growth, differentiation, and survival. We now show that Notch1-IC suppresses the scaffold activity of c-Jun N-terminal kinase (JNK)-interacting protein 1 (JIP1) in the JNK signaling path-way. Notch1-IC physically associated with the JNK binding domain of JIP1 and thereby interfered with the interaction between JIPI and JNK. JIP1 mediated the activation of JNK1 induced by glucose deprivation in mouse embryonic fibroblasts, and ectopic expression of Notch1-IC inhibited INK activation and apoptosis triggered by glucose deprivation. Taken together, these findings suggest that Notch1-IC negatively regulates the JNK pathway by disrupting the scaffold function of JIP1. [ABSTRACT FROM AUTHOR]