Research Report 2010 - MDC

Basic Cardiovascular FunctionStructure of the GroupThomas E. WillnowGroup LeaderProf. Dr. Dr. Thomas E. WillnowScientistsDr. Tilman BreiderhoffDr. Anne-Sophie CarloDr. Juliane ReicheDr. Michael RoheDr. Vanessa SchmidtGraduate StudentsTilman Burgert*Safak Caglayan*Anna Christa*Molecular Cardiovascular ResearchVPS10P domain receptors such as SORLA and sortilin comprise a recently identified class ofintracellular sorting proteins that are predominantly expressed in neurons but also in nonneuronalcell types. VPS10P domain receptors were previously considered to be orphan receptorswith activities in neuronal protein trafficking that were poorly understood. However, newfindings revealed unexpected roles for these receptors as regulators of neuronal viability andfunction. Recent work from our laboratory has uncovered the molecular mechanisms of regulatedprotein transport and signaling through VPS10P domain receptors. Loss of this regulation maycontribute to devastating disorders of the nervous system, including Alzheimer disease, affectivedisorders, and cell death following spinal cord injury. We also obtained first encouraging dataconcerning possible roles for these receptors in regulation of the cardiovascular system.IntroductionThe VPS10P domain is a protein module that was firstrecognized in the vacuolar protein sorting 10 protein(VPS10P) in Saccharomyces cerevisiae. VPS10P is a sortingreceptor that directs the trafficking of lysosomalenzymes from the Golgi to the vacuole (the lysosome inYeast). Subsequently, this protein domain was found toconstitute the unifying structural feature of a newgroup of type 1-membrane receptors that are conservedthroughout evolution from baker’s yeast to man. Themembers of this gene family are now known as VPS10Pdomain receptors. Five receptors are found in vertebrates:sortilin, SORLA, SORCS1, SORCS2, and SORCS3(Fig. 1A).VSP10P domain receptors were initially considered arather peculiar group of sorting proteins with unknownfunction. However, the mammalian receptors of thegene family surfaced as potential disease genes in anumber of association studies in patients. These diseasesencompass Alzheimer’s disease (AD) and othertypes of age-related dementias (in which SORLA andSORCS1 have been implicated), bipolar disorders (inwhich SORCS2 has been implicated), as well as senescenceof the nervous system (in which sortilin has beenimplicated). In addition, several common cardiovascularand metabolic disorders involving VPS10P domainreceptors were identified including type 2 diabetes(which has been linked to SORCS1 and SORCS3) as well asdyslipidemia, and myocardial infarction (which havebeen linked to sortilin).Subcellular trafficking of VPS10P domainreceptorsThe trans-Golgi network (TGN) is an organelle that isimportant for the distribution of proteins between variouscellular compartments. It serves to direct newlysynthesized proteins into constitutive or regulatedsecretion. It sorts proteins into endosomal or lysosomalcompartments, and it participates in axonal transportand the action of signaling endosomes in neurons.Given its structural similarity to VPS10P, a sorting receptorin the TGN, a similar function for SORLA in Golgitrafficking had been anticipated. Our recent data on the6 Cardiovascular and Metabolic Disease Research