Sortilin, a regulator of neuronal viability and hepatic lipoprotein production
Introduction. Nerve growth factor (NGF) signals through receptors TrkA and p75NTR to regulate neuronal survival and differentiation (Fig. 7). Intriguingly, its precursor proNGF has the opposite function and induces cell death under acute or chronic distress of the NS. However, the receptor(s) responsible for proNGF-induced apoptosis remained unclear.
Based on cell studies, we argued that proNGF signals through a receptor complex composed of p75NTR and sortilin, a member of the Sortilin gene family (Nykjaer et al., Nature, 2004) (Fig.7). In collaboration with the group of Anders Nykjaer (University Aarhus), we now resolved the complex functions of sortilin in regulation of neuronal viability in vivo. These findings contributed to our understanding of NGF action (Willnow et al., Nat Reviews Neurosci, 2008), but also identified sortilin as drug target in neurological diseases – a concept that we follow up in the biotech venture NeuronIcon.
Sortilin controls neuronal survival. Initially, we generated a sortilin-deficient mouse to test contributions of this receptor to neuronal viability in vivo. Sortilin deficiency prevented age-dependent degeneration of sympathetic neurons and protected motor neurons from death in spinal cord injury. These findings confirmed distinct roles for sortilin in proNGF-induced apoptosis in pathological conditions but also in ageing of the NS (Jansen et al., Nat Neurosci, 2007).
Unexpectedly, some phenotypes in sortilin-/- mice indicated impaired trophic support by mature NGF. The underlying mechanism was revealed when we demonstrated that sortilin also interacts with TrkA and enables its anterograde axonal transport to enhance NGF signaling. The trophic action of sortilin was confirmed in mice heterozygous for the TrkA null allele as deficiency for sortilin aggravated their TrkA deficiency phenotype (sympathetic neuropathy) (Vaegter et al., Nat Neurosci, 2011) (Fig.7).
Role in hepatic lipoprotein metabolism. An unexpected role for sortilin in lipoprotein metabolism was suggested by recent GWAS that revealed an association of hypercholesterolemia with SNPs on 1p13.3, a locus that includes SORT1 (encoding sortilin). We demonstrated that sortilin acts as a sorting receptor for apolipoprotein B100 in the liver, facilitating hepatic export of lipoproteins and regulating plasma cholesterol levels. Absence of sortilin in mice reduced hepatic secretion of lipoproteins and ameliorated the hypercholesterolemia in LDL receptor-/- animals. In contrast, overexpression stimulated release of lipoproteins and increased plasma cholesterol levels. Although some controversy in the literature still remains to be resolved, our findings suggest a novel function for sortilin in the regulation of cellular lipoprotein production (Kjoelby et al., Cell Metab, 2010).