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RESEARCH HIGHLIGHTS Disease Models & Mechanisms Disease Models & Mechanisms DMM Neurodegenerative disease: neurons don’t take all of the blame for ALS Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disease resulting in paralysis and usually death within less than 5 years of onset. Inherited forms of ALS are most often associated with expression of a dominant mutated form of superoxide dismutase (SOD1) which is toxic to motor neurons, causing them to die prematurely. To determine the role of mutated SOD1 in the progression of ALS, Yamanaka et al. engineered a chimeric mouse model in which the expression of mutant SOD1 was isolated to motor neurons and oligodendrocytes. They report that the presence of the surrounding ‘normal’ cells, not expressing mutated SOD1, inhibits the progression of neurodegeneration and increases disease-free life span when compared with mice that ubiquitously express mutant SOD1. This indicates that many different cell types, in addition to motor neurons and oligodendrocytes, contribute to the onset and progression of ALS and the interaction of cell types should be considered when determining the potential of future therapeutics. A C-type lectin domain family 5 (CLEC5A) on the surface of macrophages has now been identified that interacts with an envelope protein on the dengue virus to specifically induce the production of proinflammatory cytokines by macrophages during infection. A collaboration of researchers in Taiwan used a monoclonal antibody to block CLEC5A, and demonstrate that inhibiting this macrophage-virus interaction prevents plasma leakage and hemorrhage in a mouse model. The antibody had an overall pro-survival effect suggesting that this strategy may prove effective for inhibiting severe inflammation and shock associated with certain viral infections. TORC, which stimulates CREB activation in the brain during starvation. Their recent report illustrates that TORC mutant flies are more sensitive to oxidative stress and starvation and exhibited reduced stores of carbohydrates and fat. Thus, TORC is necessary to maintain normal energy balance in flies. TORC genes (target of rapamycin (TOR) complexes) are highly conserved and orthologs exist in organisms ranging from algae to humans and recent studies show an important role for TOR kinases in metabolism and aging in yeast. Thus, related kinases may prove important in human glucose metabolism and oxidative stress response. Chen, S. T., Lin, Y. L., Huang, M. T., Wu, M. F., Cheng, S. C., Lei, H. Y., Lee, C. K., Chiou, T. W., Wong, C. H. and Hsieh, S. L. (2008). CLEC5A is critical for denguevirus-induced lethal disease. Nature 453, 672-676. Wang, B., Goode, J., Best, J., Meltzer, J., Schilman, P. E., Chen, J., Garza, D., Thomas, J. B. and Montminy, M. (2008). The insulin-regulated CREB coactivator TORC promotes stress resistance in Drosophila. Cell Metab. 7, 434-444. Metabolism: TORCing neurons to maintain blood glucose Yamanaka, K., Boillee, S., Roberts, E. A., Garcia, M. L., McAlonis-Downes, M., Mikse, O. R., Cleveland, D. W. and Goldstein, L. S. (2008). Mutant SOD1 in cell types other than motor neurons and oligodendrocytes accelerates onset of disease in ALS mice. Proc. Natl. Acad. Sci. USA 105, 7594-7599. Image courtesy of Matthew Freeman. Infectious disease: taking the shock out of hemorrhagic fever Some of the most deleterious effects associated with dengue-virus infection result from induction of proinflammatory cytokines and overstimulation of the immune system. Cytokines make blood vessels leaky and promote inflammation of tissues, which can lead to internal hemorrhaging and loss of blood fluid from the vasculature, which can result in shock. Macrophages are a major producer of proinflammatory cytokines and a primary target of dengue virus infection. Disease Models & Mechanisms Insulin serves as a master switch to finely regulate circulating glucose levels despite regular intervals of fasting and eating, by manipulating signaling pathways. Glucose homeostasis requires the generation and maintenance of glycogen and lipid stores that are utilized in times of fasting or starvation. Low levels of circulating glucose in Drosophila and mammals causes the evolutionarily conserved signaling protein, cAMP response element-binding protein (CREB), to stimulate the production of glucose from noncarbohydrate sources, such as fat or amino acids. Collaborative work between researchers at UCSD, Novartis and the Salk Institute have identified a CREB coactivator in Drosophila, Heart disease and stem cells: new sources of hope for troubled hearts Two distinct populations of cells have previously been identified as cardiac progenitors, giving rise to different areas of the developing heart. Scientists in the USA and the UK have now come together to add a third myocardial lineage to the list. A recent report from Cai et al. has identified pluripotent cardiac cells in mice that develop into myocytes in the heart wall in addition to cardiac fibroblasts and coronary smooth muscle cells. These stem cells originate in the proepicardium and express the T-box transcription factor Tbx18, which is also found at sites of heart regeneration in zebrafish. The identification of new cardiac stem cell populations should lead to better understanding the mechanisms underlying heart development and congenital defects. As we accumulate information on how these cells maintain pluripotency and differentiate, they may play an important role in regenerative medicine for congenital defects or acquired heart disease. Cai, C. L., Martin, J. C., Sun, Y., Cui, L., Wang, L., Ouyang, K., Yang, L., Bu, L., Liang, X., Zhang, X., Stallcup, W. B., Denton, C. P., McCulloch, A., Chen, J. and Evans, S. M. (2008). A myocardial lineage derives from Tbx18 epicardial cells. Nature May 14 [Epub ahead of print] [doi 10.1038]. 1 RESEARCH HIGHLIGHTS Cancer: cilia, cysts and renal cell carcinoma Disease Models & Mechanisms tion. Although the mechanisms by which these pathways are activated in VHL patients are incompletely understood, this opens the possibility that inhibition of PI3K or ERK signaling pathways may prove effective therapeutic strategies to prevent the loss of primary cilia and inhibit cyst formation and ccRCC formation in VHL patients. Frew, I. J., Thoma, C. R., Georgiev, S., Minola, A., Hitz, M., Montani, M., Moch, H. and Krek, W. (2008). pVHL and PTEN tumour suppressor proteins cooperatively suppress kidney cyst formation. EMBO J. May 22 [Epub ahead of print] [doi: 10.1038/emboj.2008.96]. Disease Models & Mechanisms DMM Image reproduced from Development (2005) 132, (12). Mutations in the von Hippel-Lindau tumor suppressor gene (VHL) predispose patients to develop both renal cysts and clear cell renal cell carcinoma, albeit with relatively low frequency, a finding that has been recapitulated in mice mutant for the Vhlh gene. This has led to the view that additional mutations are required to cause progression to cysts or carcinoma in VHL disease. Work in the lab of Wilhelm Krek and colleagues at ETH Zurich shows that cysts from patients with VHL disease exhibit increased activation of phosphoinositide 3-kinase (PI3K). Because the Pten tumor suppressor normally antagonizes PI3K signaling, they combined conditional inactivation of both the Vhlh and Pten tumor suppressor gene in the mouse kidney, and found this caused cyst formation after short latency. Interestingly, the cells lining these cysts frequently lacked a primary cilium, a structure thought to be involved in suppressing cellular prolifera- 2 Neurodegenerative disease: cleaning out Alzheimer’s by autophagy Autophagy (literally, self-eating) is a major cellular pathway by which long-lived cellular proteins, protein aggregates, and organelles are degraded. Proteins targeted for destruction by this pathway are first recruited into double-membrane vesicles called autophagosomes, and are delivered from there to lysosomes. Beclin 1 is critical for autophagosome formation, and mutant mice heterozygous for a deletion of beclin 1 show reduced autophagosome production. Alzheimer’s disease, like other neurodegenerative diseases, is characterized by the presence of protein aggregates and the presence of autophagosomes in dystrophic neurites; however, whether autophagy is protective or detrimental is unclear. In an international collaboration including researchers from Stanford University, Image reproduced from J. Cell Sci. (2007) 120, (23). University of California, San Diego, Freie Universitaet Berlin, Columbia University, University of Texas Southwestern Medical Center, and the VA Palo Alto Heath Care System, Pickford et al. present a series of experiments suggesting that reduced beclin 1 decreases neuronal autophagy and exacerbates the Alzheimer’s-like phenotypes of APP transgenic mice. Thus, autophagy may be protective and increasing beclin-1 levels may provide therapeutic benefit in Alzheimer’s disease. Pickford, F., Masliah, E., Britschgi, M., Lucin, K., Narasimhan, R., Jaeger, P. A., Small, S., Spencer, B., Rockenstein, E., Levine, B. and Wyss-Coray, T. (2008). The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. J. Clin. Invest. 118, 2190-2199. dmm.biologists.org