Biology subjects

Lam, V. Y. M.

Publications and source records attributed to Lam, V. Y. M..

3 recordsLinked to original sources

bioRxiv2021

A Non-Canonical Raf Function Is Required for Dorsal-Ventral Patterning During Drosophila Embryogenesis

Proper embryonic development requires directional axes to pattern cells into embryonic structures. In Drosophila, spatially discrete expression of transcription factors determines the anterior to posterior organization of the early embryo, while the Toll and TGF{beta} signalling pathways determine the early dorsal to ventral pattern. Embryonic MAPK/ERK signaling contributes to both anterior to posterior patterning in the terminal regions and to dorsal to ventral patterning during oogenesis and embryonic stages. Here we describe a novel loss of function mutation in the Raf kinase gene, which leads to loss of ventral cell fates as seen through the loss of the ventral furrow, the absence of Dorsal/NF{kappa}B nuclear localization, the absence of mesoderm determinants Twist and Snail, and the expansion of TGF{beta}. Gene expression analysis showed cells adopting ectodermal fates much like loss of Toll signaling. Our results combine novel mutants, live imaging, optogenetics and transcriptomics to establish a novel role for Raf, that appears to be independent of the MAPK cascade, in embryonic patterning.

developmental biology↗

bioRxiv2019

Application of Optogenetic Amyloid-β Distinguishes Between Metabolic and Physical Damage in Neurodegeneration

The brains of Alzheimers Disease patients show a decrease in brain mass and a preponderance of extracellular Amyloid-{beta} plaques. These plaques are formed by aggregation of polypeptides that are derived from Amyloid Precursor Protein (APP). Amyloid-{beta} plaques are thought to play either a direct or an indirect role in disease progression, however the exact role of aggregation and plaque formation in the ethology of Alzheimers Disease is subject to debate, not least because the biological effects of soluble and aggregated Amyloid-{beta} peptides are difficult to separate in vivo. To investigate the consequences of formation of Amyloid-{beta} oligomers in living tissues, we developed a fluorescently tagged, optogenetic Amyloid-{beta} peptide that oligomerizes rapidly in the presence of blue light. We applied this system to the crucial question of how intracellular Amyloid-{beta} oligomers underlie the pathologies of Alzheimers Disease. We show that, although both expression and induced oligomerization of Amyloid-{beta} were detrimental to lifespan and healthspan, we were able to separate the metabolic and physical damage caused by light-induced Amyloid-{beta} oligomerization from Amyloid-{beta} expression alone. The physical damage caused by Amyloid-{beta} oligomers also recapitulated the catastrophic tissue loss that is a hallmark of late AD. We show that the lifespan deficit induced by Amyloid-{beta} oligomers was reduced with Li+ treatment. Our results present the first model to separate different aspects of disease progression.

developmental biology↗

bioRxiv2017

Slowing ageing using drug synergy in C. elegans

Pharmacological interventions that target human ageing would extend individual healthspan and result in dramatic economic benefits to rapidly ageing societies worldwide. For such interventions to be contemplated they need to comprise drugs that are efficacious when given to adults and for which extensive human safety data are available. Here we show that dramatic lifespan extension can be achieved in C.elegans by targeting multiple, evolutionarily conserved ageing pathways using drugs that are already in human use. By targeting multiple synergistic ageing pathways, we are able to slow ageing rate, double lifespan and improves healthspan while minimize developmental and fitness trade-offs. Moreover, we established that there is no synergistic benefit in a daf-2 or daf-7 background, implying the involvement of the TGF{beta} and IGF pathways in this synergy. Employing lipidomics and transcriptomics analysis we found lipid metabolism to be affected resulting in increased monounsaturated fatty acids (MUFA) and decrease membrane peroxidation index. Our best drug combination showed a conserved lifespan extension in fruit flies. To the best of our knowledge, this is the largest lifespan effect ever reported for any adult-onset drug treatment in C. elegans. This drug-repurposing approach, using drugs already approved for humans to target multiple conserved aging pathways simultaneously, could lead to interventions that prevent age-related diseases and overall frailty in a rapidly ageing population.

biochemistry↗