Defining the role of retromer in endosomal sorting in health and disease. (360G-Wellcome-104568_Z_14_Z)

This proposal focuses on an ancient, highly conserved protein complex composed of VPS26, VPS29 and VPS35, here termed retromer, that functions as a molecular machine controlling the endosomal sorting of numerous transmembrane spanning proteins (termed cargoes) to the plasma membrane, trans-Golgi network (TGN) or specialised organelles (e.g. lysosome and lysosome-related organelles) [1,2]. Retromer is present in every eukaryotic cell and knock-outs in model organisms are unviable1 as retromer reg ulates sorting of cargoes involved in establishment of epithelial polarity [3] and formation of morphogenic gradients [4-6]. Retromer is also associated with disease, being hijacked by various pathogens [7,8] and necessary for non-amyloidogenic processing of amyloid precursor protein [9]. More recently, a retromer mutation, VPS35(p.D620N), and mutations in retromer-associated proteins, have been linked with familial late onset Lewy body Parkinsons disease (PD) [10-13]. These patients lack discer nible symptoms prior to clinical diagnosis [14], implying that retromer pathway mutations pre-dispose dopaminergic neurones to age-related neurodegeneration, likely arising from an altered ability of retromer to control sorting of neuroprotective cargoes. Evidence of reduced retromer expression in brains of sporadic PD patients [12] further supports this hypothesis. With Wellcome Trust support we will address two related questions: o The fundamental question of how retromer functions as a machine to regulate endosomal sorting. o Apply acquired knowledge to establish how retromers activity is perturbed in PD, thereby providing vital insight into the underlying cell biology of this disease.