Willnow Lab

Using transgenic mouse strains and human stem cell-derived models we study the molecular mechanisms connecting energy balance with development and functional integrity of the nervous system, and why disturbances in these mechanisms cause diseases of the metabolism and the brain.

Receptor-mediated endocytosis is the main mechanism whereby cells take up essential metabolites and signaling molecules. Consequently, dysfunctions of endocytic receptors are the cause of many devastating diseases in humans.

Our group focuses on the functional characterization of endocytic receptors specifically expressed in neurons, elucidating the significance of these receptor pathways for embryonic development, for functional integrity, and for degenerative diseases of the central nervous system.

Mainly using transgenic cell and mouse models, we currently study the involvement of endocytic receptor pathways in two main projects.  In the first project, we characterize the role of endocytic receptors in developmental defects of the forebrain, an anomaly affecting as many as 1 in 250 human pregnancies. In the second major project, we explore endocytic pathways in neurons that are the underlying cause Alzheimer’s disease, a neurodegenerative disease that impacts millions of patients worldwide.

Receptor-mediated endocytosis is the main mechanism for selective transport of macromolecules into cells. Significant progress has been made in elucidating the various steps of endocytosis at the cellular level. However, the physiological relevance of many endocytic pathways for organ function remains elusive.

We study orphan endocytic receptors expressed in the central nervous system to uncover their roles during development but also in neurodegenerative diseases of the brain.

The main class of endocytic receptors is the LDL receptor gene family (Fig. 1). The prototype of the gene family is the LDL receptor that mediates uptake of cholesterol-rich lipoproteins. Since other family members also bind lipoproteins, roles for these receptors in lipid metabolism had been anticipated. Surprisingly, studies in previous years uncovered many more functions performed by these receptors, changing our perception of lipoprotein receptors from mere cargo transporters to key regulators of numerous physiological processes. In particular, the significance of these receptors for development and functional integrity of the central nervous system is noteworthy. Yet, studies so far provided just a glimpse at their contributions to neurobiology, with many details still to be uncovered.

Fig. 1: LDL receptor and sortilin gene families

Whereas studies on the LDL receptor gene family yielded exciting insights into the significance of endocytosis for neuronal signaling, identification of another group of orphan receptors called sortilins directed our attention to the role of receptors in intracellular protein transport in neurons. The founding member of this new gene family is SORLA, a receptor that shares structural elements of the LDL receptor gene family (Fig. 1). In addition, it includes a VPS10P domain initially identified in the vacuolar protein sorting 10 protein, a sorting receptor in yeast. Subsequent identification of four other mammalian proteins that share the VPS10P domain suggested the existence of a new class of neuronal receptors that act in endocytosis and/or intracellular protein transport. Their functions remained poorly characterized.

In recent years, work from our group has significantly contributed to a deeper understand of the role of endocytic receptors in normal physiological processes and in inherited diseases of the human brain. Specifically, we focused on three receptors, namely LRP2, SORLA, and sortilin.

2015 - Hiddensee

2013 - Climb-up

2012 - BBQ

2011 - Trip to Anholt