Research Report 2010 - MDC

Figure 2: SORLA and sortilin in neuronal protein transport and signaling. (A) Role of SORLA in trafficking and processing of APP. In neurons, newlysynthesized APP molecules traverse the trans-Golgi network (TGN) en route to the plasma membrane (1). The precursor proteins internalize fromthe cell surface (2) and traffic from early to late endosomes for processing into Aβ (3). SORLA acts as sorting receptor that traps APP in the TGN,reducing the number of precursor molecules that can reach the cell surface and enter endocytic processing pathways (4). In addition, APP moleculesthat reach the cell surface and enter early endosomes are shuttled by SORLA back to the TGN, further reducing the extent of Aβ production inlate endosomes (5). (B) Role of sortilin in (pro)neurotrophin action. Mature NGF binds to a heteromeric complex of TrkA and p75 NTR that stimulatessignaling pathways promoting cell survival. In contrast, proNGF engages a dual receptor complex consting of sortilin and p75 NTR that elicits neuronalcell death.amyloid β peptide (Aβ) through sequential cleavage byβ- and γ-secretases. In the brain, Aβ forms neurotoxicoligomers and amyloid plaques, the pathological hallmarksof AD. Using cell culture and transgenic mousemodels we elucidated the mechanisms of SORLA actionin neurodegenerative processes in molecular detail.According to our data, SORLA acts as intracellular sortingreceptor for APP that controls trafficking of the precursorprotein between TGN and early endosomes. Inparticular, SORLA blocks export of APP from the TGNinto post-Golgi compartments that harbor β-secretaseactivity and thus impairs formation of Aβ (Fig. 2A).Consequently, genetic overexpression of SORLA in culturedneurons results in reduced processing of APP intoAβ. In contrast, disruption of the receptor gene inmouse models of AD significantly increased Aβ productionand plaque formation, similar to the situation inpatients with sporadic AD.Sortilin controls neuronal cell deathAs part of a collaborative project with the laboratory ofAnders Nykjaer from Aarhus University, we uncoveredthe role of sortilin in the action of neurotrophins (NTs).NTs are growth factors that regulate neuronal survival,axon and dendrite specification, and target innervation.In mammals, the NT family includes nerve growth factor(NGF), brain-derived nerve growth factor (BDNF), aswell as NT-3 and -4/5. Their trophic action is mediatedby binding to receptor tyrosine kinases (called Trk receptors)and to the common p75 neurotrophin receptor(p75 NTR ). All NTs are synthesized as proneurotrophins(proNTs) that are subsequently processed to theirmature counterparts in the TGN. Paradoxically, whilemature neurotrophins promote neuronal survival bybinding to Trk receptors and p75 NTR , proneurotrophinsinduce apoptosis when released from cells.8 Cardiovascular and Metabolic Disease Research