Stacey Williams et al. (2007) International Worm Meeting "LITE-1: a novel light receptor that mediates the C. elegans light response and the light - driven rescue of paralyzed synaptic signaling mutants."

Nicole Charlie, Brandon Brown, Kenneth Miller, Marie Milfort, Christen Gravlin, Jamie Knecht, Stacey Williams

[International Worm Meeting, 2007]

C. elegans is often described as a soil organism and is not known to need a response to light. However, we found that C. elegans has a robust locomotory response to blue and shorter wavelengths of light, with maximal sensitivity to UV light. The light response does not correlate with light-induced temperature changes. It is present from birth onward, including dauers, and is a survival strategy, because extended illumination with blue and shorter wavelengths kills C. elegans by a temperature-independent mechanism. The light response has the astonishing ability to restore wild type levels of coordinated locomotion to mutants with strongly impaired presynaptic G<font face=symbol>a</font>q or G<font face=symbol>a</font>s pathways, which are nearly paralyzed under normal light conditions, but it cannot rescue similarly paralyzed mutants with defects in synaptic vesicle priming. Using a forward genetic screen we identified LITE-1, an eight-transmembrane protein and member of the large Gustatory Receptor family, as the major mediator of the light response. Pan-neuronal expression of LITE-1 rescues a lite-1 null mutant, but activation of LITE-1 just in tail neurons also fully rescues the light response and the light-driven rescue of paralyzed synaptic signaling mutants. LITE-1 has no homology to G protein - coupled receptors, and our 20-fold coverage genetic screen did not identify a G<font face=symbol>a</font> protein involved in the response. Transgenic expression of LITE-1 in body wall muscles causes a tissue that is normally light-insensitive to become light-sensitive, thus demonstrating that LITE-1 is a light receptor. The light sensitivity takes the form of a powerful contraction of muscle cells that begins within 300 msec of exposure to short-wavelength light. We are currently using Cameleon FRET imaging of cultured muscle cells to test whether LITE-1 is coupled to the opening of calcium channels or the release of calcium from internal stores, and we are attempting to identify the source of calcium using various genetic and pharmacological tools. Our results reveal a novel sensory modality in C. elegans that is mediated by a new kind of light receptor coupled to a novel signal transduction mechanism involving calcium mobilization.

Wu Y et al. (2010) Neurobiol Aging "Heat shock treatment reduces beta amyloid toxicity in vivo by diminishing oligomers."

Cao Z, Klein WL, Luo Y, Wu Y

[Neurobiol Aging, 2010]

Heat shock response, mediated by heat shock proteins, is a highly conserved physiological process in multicellular organisms for reestablishment of cellular homeostasis. Expression of heat shock factors and subsequent heat shock protein plays a role in protection against proteotoxicity in invertebrate and vertebrate models. Proteotoxicity due to beta-amyloid peptide (Abeta) oligomerization has been linked to the pathogenesis of Alzheimer's disease. Previously, we demonstrated that progressive paralysis induced by expression of human Abeta(1-42) in transgenic Caenorhabditis elegans was alleviated by Abeta oligomer inhibitors Ginkgo biloba extract and its constituents [Wu, Y., Wu, Z., Butko, P., Christen, Y., Lambert, M.P., Klein, W.L., Link, C.D., Luo, Y., 2006. Amyloid-beta-induced pathological behaviors are suppressed by Ginkgo biloba extract EGb 761 and ginkgolides in transgenic Caenorhabditis elegans. J. Neurosci. 26(50): 13102-13113]. In this study, we apply a protective heat shock to the transgenic C. elegans and demonstrate: (1) a delay in paralysis, (2) increased expression of small heat shock protein HSP16.2, and (3) significant reduction of Abeta oligomers in a heat shock time-dependent manner. These results suggest that transient heat shock lessens Abeta toxicity by diminishing Abeta oligomerization, which provides a link between up regulation of endogenous chaperone proteins and protection against Abeta proteotoxicity in vivo.

Sandrine Fraboulet et al. (2009) European Worm Neurobiology Meeting "Chemical rescue of paralysis in a transgenic model of Caenorhabditis elegans overexpressing human Beta-amyloid"

David I C Scopes, Andrew K Jones, David B Sattelle, Aileen Moloney, Christopher D Link, Steven D Buckingham, Mark J Treherne, Hozefa Amijee, Sandrine Fraboulet

[European Worm Neurobiology Meeting, 2009]

Authors acknowledge support from MRC. Numerous studies support a role for aggregated Ab as a mediator of the toxicity that underlies Alzheimer.s disease (AD) and other diseases such as Inclusion Body myositis (IBM), an acquired muscle disease affecting people over 50 years old. In this pathology, muscle weakness and degeneration is accompanied by chronic muscle inflammation. Remarkably, despite the inflammation component of the disease, IBM patients are only poorly responsive to anti-inflammatory drugs suggesting that inflammation per se may not be the primary cause of the pathology. We have used a C. elegans transgenic line over-expressing human amyloid 1-42 peptide in the muscles as a model with which to test the efficiency of new compounds on in vivo amyloid toxicity. This C. elegans line becomes paralyzed shortly after the induction of amyloid expression in the muscles, which makes it an easily-recordable phenotype useful for exploring candidate treatments to alleviate the paralysis. We report on the actions of two novel chemicals, which inhibit amyloid aggregation and partially rescue the amyloid-induced phenotype. References: Wu Y, W.Z., Butko P, Christen Y, Lambert MP, Klein WL, Link CD, Luo Y. (2006) J. Neurosci., 26, 13102-13. Link CD, T.A., Kapulkin V, Duke K, Kim S, Fei Q, Wood DE, Sahagan BG. (2003) Neurobiol Aging., 24, 397-413. Jones, A.K., Buckingham, S.D. and Sattelle, D.B. (2005). Nat Rev Drug Discov, 4, 321-30.