MIND
“Membrane-receptors In Neuronal Disease”

MIND is a neuroscience research-centre at the University of Aarhus. The centre was founded November 1’st 2005 by groups at the Faculties of Medicine and Natural Sciences in Aarhus, and is sponsored by a major grant from The Lundbeck Foundation. MIND is dedicated to multidisciplinary basic research in the molecular function and physiological role of the Vps10p-domain (Vps10p-D) receptors, a newly defined family of mammalian type-1 receptors.

Figure 1. Schematic drawing of the Vps10p domain receptor family

The family contains five members, Sortilin, SorLA and SorCS1-3, that are all particularly expressed in developing and adult neuronal tissue. Their common characteristic, the hallmark of the family, is the Vps10p-domain named after the yeast sorting protein Vps10p. This domain is not found in other mammalian proteins and is remarkable in the sense that it binds a number of ligands, notably neurotrophic growth factors and peptides. The latter include (pro)NGF, (pro)BDNF, GDNF and neurotensin, factors that are needed for the differentiation of nerve cells and to sustain normal function of the nervous system.

Figure 2. A schematic model showing receptor complex formation in reponse to proNGF (Sortilin and p75NTR) and NGF (TrkA and p75NTR). Cells secrete both proNGF and mature NGF. If proNGF does not bind to a Sortilin-p75NTR heterodimer, limited proteolysis may convert the precursor to mature NGF, which subsequently can bind to a complex of TrkA and p75NTR.

 

The receptors may also form functional complexes with certain transmembrane proteins, e.g. the p75 neurotrophin receptor and the amyloid precursor protein (APP), and target ligands in intracellular compartments as well as on the cell surface. They partake in both protein sorting and signal transduction, and these capacities lend them a role in mechanisms that regulate cellular death and survival. Accordingly, recent findings implicate Vps10p-D receptors in the generation of posttraumatic neuronal apoptosis and the generation of Alzheimers disease.

Figure 3. Schematic overview of how SorLA influences APP and BACE interaction. SorLA likely regulates trafficking of APP through the Golgi, mainly through slowing release of the precursor to the cell surface and blocking interaction with BACE. Only those APP molecules that are released by SorLA are accessible for proteolytic cleavage either in the Golgi or distal cellular compartments. Following BACE –mediated proteolysis, a g-secretase (not depicted) finally releases the Ab from the cell (modified from Spoelgen R. et al. (2006) J. Neurosci. 26:418-428).

The centre aims to expand ongoing biochemical and cell biological analysis of the Vps10p-D receptors with a broad variety of techniques and new angles of approach, and to incorporate activities ranging from protein crystallography to studies of transgenic animal models. It is the intention of MIND to explore all major aspects of this receptor family and to establish a link between the molecular and cellular function(s) of the individual receptors and their ultimate physiological role(s).