Sandbox Reserved 938: Difference between revisions

MANF knock-out mouse has been generated and characterized, the results were published very recently, revealing a very intruiging phenotype, further confirming the beforementioned interactions and structure/function relations. Namely, the global MANF knock-out develops a severe case of diabetes due to increased ER-stress response (Lindahl et al, 2014). The roles of MANF, proposed by the crystal structure of the C-terminal domain, have thus been confirmed by the in vivo studies. In part it makes the perfect sense - namely secretion of proteins is a very demanding procedure and the total amount of proteins that pancreas needs to produce and secrete is humongous. This means that the secretory cells have a much higher basal stress level than non-secreting cells. The more proteins are produced the higher the chance and also absolute amount of misfolded and/or unfolded proteins amassed that needs to be dealt with by the intracellular machinery. If now further damage is caused to these reparatory cascades the higher the chance for the cell to reach a point of no return and the UPR becoming too overwhelming and thus the cell goes into apoptosis. As expected thus, Lindahl et al. show the increased amount of TUNEL-positive pancreatic beta cells in MANF knock-out animals, confirming that eventually, beta cells undergo programmed cell death in response to increased ER-stress.