Muliyil, S. | Search bioRxiv

bioRxiv2020

ADAM17-triggered TNF signalling protects the ageing Drosophila retina from lipid droplet mediated degeneration

Animals have evolved multiple mechanisms to protect themselves from the cumulative effects of age-related cellular damage. Here we reveal an unexpected link between the TNF (tumour necrosis factor) inflammatory pathway, triggered by the metalloprotease ADAM17/TACE, and a lipid droplet (LD)-mediated mechanism of protecting retinal cells from age related degeneration. Loss of ADAM17, TNF and the TNF receptor Grindelwald in pigmented glial cells of the Drosophila retina leads to age related degeneration of both glia and neurons, preceded by an abnormal accumulation of glial LDs. We show that the glial LDs initially buffer the cells against damage caused by neuronally generated reactive oxygen species (ROS), but that in later life the LDs dissipate, leading to the release of toxic peroxidated lipids. Finally, we demonstrate the existence of a conserved pathway in human iPS-derived microglia-like cells, which are central players in neurodegeneration. Overall, we have discovered a pathway mediated by TNF signalling acting not as a trigger of inflammation, but as a cytoprotective factor in the retina.

neuroscience↗

bioRxiv2017

Somatic developmental defects in dmrad51/spnA mutant show low temperature sensitivity with enhanced genomic damages and cell death

Homologous Recombination (HR) is one of the key pathways to repair Double Strand Breaks (DSBs). Rad51 serves an important function of catalysing strand exchange between two homologous chromosomes in the HR pathway. In higher organisms, Rad51 function is indispensable with its absence leading to early embryonic lethality, thus precluding any mechanistic probing of the system. In contrast, absence of Drosophila rad51 (Dmrad51/spnA) has been associated with defects in female germline causing ventralization of the egg, without any reported detrimental consequences to Drosophila somatic tissues. In this study, we have performed a systematic analysis of somatic development of dmrad51 null mutant flies by using genetic complementation between multiple dmrad51 alleles. Our current study, for the first time, uncovers the requirement of Dmrad51 in somatic tissue maintenance at both larval and pupal stages. Also, we show that dmrad51 mutant exhibit patterning defects in abdominal cuticle in the stripes and bristles, while there appears to be only subtle defects in the adult wing and eye. Interestingly, dmrad51 null mutant and other alleles show discernible phenotype of low temperature sensitivity, suggesting a role for Dmrad51 in temperature sensitive cellular processes, which thus presents an elegant system for probing temperature sensitive cellular/tissue responses that ensue when a mutation leads to the loss of protein expression (null mutant) rather than its altered protein structure.

developmental biology↗