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Brennan, S.

Publications and source records attributed to Brennan, S..

2 recordsLinked to original sources

C. elegans processes sensory information to choose between freeloading and self-defense strategies

Hydrogen peroxide is the preeminent chemical weapon that organisms use for combat. Individual cells rely on conserved defenses to prevent and repair peroxide-induced damage, but whether similar defenses might be coordinated across cells in animals remains poorly understood. Here, we identify a neuronal circuit in the nematode Caenorhabditis elegans that processes information perceived by two sensory neurons to control the induction of hydrogen-peroxide defenses in the organism. We found that catalases produced by Escherichia coli, the nematodes food source, can deplete hydrogen peroxide from the local environment and thereby protect the nematodes. In the presence of E. coli, the nematodes neurons signal via TGF{beta}-insulin/IGF1 relay to target tissues to repress expression of catalases and other hydrogen-peroxide defenses. This adaptive strategy is the first example of a multicellular organism modulating its defenses when it expects to freeload from the protection provided by molecularly orthologous defenses from another species.

neuroscience

Identification of drug modifiers for RYR1 related myopathy using a multi-species discovery pipeline

Ryanodine receptor type I-related myopathies (RYR1-RMs) represent the largest group of non-dystrophic myopathies. RYR1-RMs are associated with severe disabilities and early mortality; despite these facts, there are currently no available treatments. The goal of this study was to identify new therapeutic targets for RYR1-RMs. To accomplish this, we developed a novel discovery pipeline using nematode, zebrafish, and mammalian cell models of the disease. We first performed large-scale drug screens in C. elegans and zebrafish. 74 positive hits were identified in C. elegans, while none were uncovered in the zebrafish. Targeted testing of these hits in zebrafish yielded positive results for two compounds. We examined these compounds using newly created Ryr1 knockout C2C12 cells, and found that p38 inhibition impaired caffeine-induced Ca2+ release. Lastly, we tested one p38 inhibitor in myotubes from Ryr1Y524S/+ (YS) mice, and demonstrated that it blunts the aberrant temperature-dependent increase in resting Ca2+ in these cells. In all, we developed a unique platform for RYR1-RM therapy development that is potentially applicable to a broad range of neuromuscular disorders.

genetics