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Investigating the trafficking and activity of the gamma-secretase complex (Sarah Bray with Maria Gomez-Lamarca)

Supervisor: Sarah Bray (with Maria Gomez-Lamarca)

The Notch pathway is one of a small handful of cell signalling pathways that coordinate development, regulating the types and numbers of cells formed in many developmental contexts. Its’ functions include maintenance of stem/progenitor cells, regulation of cell fates, organizing patterns of growth, and many others. In addition, aberrant Notch activity is implicated in diseases including cancers.

Activation of Notch involves a proteolytic cleavage by a highly conserved complex, called the gamma-secretase complex. This cuts the receptor just within the membrane to release the Notch intracellular domain, which enters the nucleus and regulates transcription. Under some circumstances this cleavage occurs when it shouldn’t, leading to inappropriate Notch activity that can cause severe defects including hyperplasia and cancers. The same gamma-secretase is also involved in cleaving other proteins and mutations in one of the subunits, presenilin are linked to Alzheimer’s disease amongst others. At the moment, it is not clear where abouts in the cells this complex is active nor how its activity is affected by other changes that predispose cells towards aberrant Notch signaling and towards defects associated with Parkinson’s disease.

Using Drosophila as a model, we propose to investigate the behaviour of the gamma-secretase by using CRISPR/Cas9 to engineer fluorescent tags on two of the subunits so their localization can be studies in the developing and aging animal. For example the aim will be introduce two types of fluorescent tags into Presenilin, that will enable us to follow the protein through the endocytic pathway. Combined with genetic approaches to alter the trafficking pathway, we will investigate how the trafficking of gamma-secretase is regulated and how this relates to situations where there is inappropriate cleavage of Notch and other key substrates.

Relevant references

Gomez-Lamarca MJ, Snowdon LA, Seib E, Klein T, Bray SJ (2015) Rme-8 depletion perturbs Notch recycling and predisposes to pathogenic signaling. J Cell Biol 210(2): 303-318 20

Xian Zhang, Yanfang Li, Huaxi Xu, Yun-wu Zhang The γ-secretase complex: from structure to function, Front Cell Neurosci. 2014; 8: 427.

Bray, SJ (2006) Notch Signalling: a simple pathway becomes complex. Nature Reviews in Molecular Cell Biology 7: 678-689.

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