Research Report 2010 - MDC

Helena Emich*Esther Kur*Daniel MilitzTechnical AssistantsChristine KruseKristin KampfMaria SchmeisserDonathe Vetter*Tatjana Pantzlaff*SecretariatVerona Kuhle*part of the period reportedFigure 1: Structural and cellular biology of VPS10P domain receptors. (A) Structural organization of VPS10P domain receptors from yeast (VPS10P)and humans (sortilin, SORLA, SORCS-1, -2, -3). (B) Cellular trafficking of SORLA. Newly synthesized receptors exit the trans-Golgi network (TGN) (1)and reach the cell surface via the constitutive secretory pathway (2). At the cell surface, they interact with the AP-2 complex to internalize viaclathrin-coated pits (3). Internalized receptors are returned to the TGN via retrograde sorting pathways, and continue subsequent shuttlingbetween endosomal and TGN compartments involving adaptor proteins GGA and PACS1 (4).cell biology of this receptor confirmed this notion (Fig.1B). SORLA is predominantly found intracellularly inendosomal vesicles and the TGN. In neurons, the receptoris concentrated in the cell body with no apparentpolarization. Receptor molecules at the plasma membraneexhibit rapid internalization that is mediated byan acidic cluster dileucine site in the cytoplasmic tail ofSORLA that interacts with the ubiquitous adaptor complexAP-2. From early endosomes, internalized receptorsare returned to the TGN (Fig. 1B). Using site-directedmutagenesis, we demonstrated that several cargoadaptors mediate the shuttling of SORLA between TGNand endosomes, including the clathrin adaptors GGA1, -2, -3 as well as PACS1 (Fig. 1B).SORLA, a key gene in Alzheimer’s diseaseSORLA is a 250-kDa protein widely expressed in neuronsof the cortex, hippocampus and cerebellum. Its involvementin Alzheimer’s disease (AD) was initially suggestedby the demonstration of low levels of Sorla geneexpression in patients suffering from the sporadic formof the disease. The association of inherited Sorla genevariants with occurrence of AD in several populationsfurther substantiated this notion. Now, our studieshave uncovered the molecular mechanism wherebySORLA controls the intracellular transport and processingof the amyloid precursor protein (APP) and contributesto AD progression.APP, a type-1 membrane protein is central to the pathologyof AD. APP is converted to a 40 to 42 amino acidCardiovascular and Metabolic Disease Research 7