Overview

The Receptor Biology of Neurodegenerative and Mental Disorders Laboratory of Anders Nykjaer, M.D., Ph.D., studies the VPS10P domain receptor family, also known as sortilins, in health and disease.

The family, which comprises sortilin, SorLA/SORL1, SorCS1, SorCS2 and SorCS3, is a group of type 1 transmembrane receptors. They are considered multifunctional as they bind a vast number of structurally unrelated proteins and engage in cellular trafficking and signaling depending on the cellular context. Among ligands identified are neurotrophins and their receptors, neuropeptides, Alzheimer's precursor protein, progranulin, ApoE, VLDL and glucose transporter 4 (GLUT4). Receptor expression predominates in neurons, but sortilins are also present in specific cell types outside the nervous system such as hepatocytes, adipocytes and immunocompetent cells.

Using biochemistry, cell biology and genetically modified mice, we have demonstrated that sortilin receptors are critical regulators of neuronal survival, differentiation, functionality and cholesterol metabolism, and their dysfunction may cause diseases both inside and outside the nervous system. Accordingly, human genetic association studies and gene targeting in mice have linked dysfunction of the receptors to schizophrenia, bipolar disorder, ADHD, Alzheimer's disease, fronto-temporal lobar dementia, cardiovascular disease and type 2 diabetes.

Through the use of transgenic mouse models and a broad repertoire of molecular, cellular and genetic tools, the goal of the Receptor Biology of Neurodegenerative and Mental Disorders Laboratory research is to unravel the function of the receptor family in both health and disease and to evaluate its drug target potential.