Willnow Lab

We study orphan endocytic receptors expressed in mammalian cell types. We elucidate their roles in (patho)physiology of the organism using transgenic mouse models, and we validate the relevance of our findings for human health and disease in studies involving patients and iPSC models thereof. In the present reporting period, we identified essential roles for endocytic receptor pathways in control of signaling by morphogens and neurotrophins, and receptor dysfunctions as cause of rare familial but also common sporadic disorders of the human brain, including developmental (holoprosencephaly), psychiatric (schizophrenia), and neurodegenerative diseases (Alzheimer’s disease). Our findings provided new paradigms in cell biology detailing how endocytic uptake and intracellular sorting of cargo represent fundamental processes to control cellular signal reception during development and in adult tissue homeostasis. Importantly, our findings uncovered endocytic receptor pathways as underlying causes for co-morbidities of the ageing brain and the metabolism, and provided explanatory models for metabolic disorders as major risk factors for neurodegenerative processes in Alzheimer’s disease.

Receptor-mediated endocytosis is the main mechanism for selective transport of macromolecules into cells. Endocytosis supplies cells with essential metabolites but also controls cellular signal reception by extracellular cues. Significant progress has been made in elucidating the various steps of endocytosis at the cellular level.

However, the relevance of many endocytic pathways for organ (dys)function in humans remains elusive.

The main class of endocytic receptors is the LDL receptor gene family that mediates uptake of cholesterol-rich lipoproteins in many cell types, a process important for cardiovascular health (Fig. 1). Surprisingly, subsequent studies uncovered additional functions performed by these receptors, changing our perception of lipoprotein receptors from mere lipid transporters to key regulators of numerous physiological processes. In particular, the emerging role of these receptors in development and functional integrity of the brain is exciting. Yet, studies so far provided just a glimpse at their manifold contributions to brain health and disease.

Fig. 1: LDL receptor and sortilin gene families. LRP, LDL receptor-related protein; SORLA, sorting protein-related receptor; SORCS, sortilin-related receptor CNS expressed.

Whereas studies on the LDL receptor gene family yielded insights into the significance of endocytosis for cellular signal transduction, identification of another group of orphan endocytic receptors, called VPS10P domain receptors or sortilins directed our attention to intracellular cargo transport as cause of human disease. Sortilins share structural similarity to a sorting receptor in yeast, suggesting their involvement in intracellular protein trafficking in mammalian cell types. While this hypothesis was confirmed by recent studies, including our own work, the many functions of sortilins in human (patho)physiology still remained to be identified.

We aim at functional characterization of orphan endocytic receptors in the cardiovascular and the nervous systems. In line with the mission of the MDC, our overall goal is to identify the physiological functions of these receptors, their implications for human diseases, and their potential as targets for therapeutic intervention. Using functional genomics, we explore the contribution of novel receptor pathways to the (patho)physiology in transgenic mouse models. We validate our hypotheses for human diseases by studies in patients and iPSC models, and we ultimately confirm the receptors’ potential as therapeutic targets in biotech spin-offs and with pharmaceutical partners.

We identified novel disease mechanisms underlying rare familial but also common sporadic forms of diseases of the human brain and metabolism. We elucidated the receptor LRP2 as a molecular cause of holoprosencephaly, the most common form of forebrain malformation in humans. We documented sortilins as novel risk factors in psychiatric and neurodegenerative diseases, and SORLA as the first familial Alzheimer’s disease (AD) gene to be uncovered in 20 years. Most importantly, we identified endocytic pathways that underlie the co-morbidity of the ageing brain and the metabolism and that offer exciting new perspectives for elucidating the metabolic basis of age-related dementia.

2015 - Hiddensee

2013 - Climb-up

2012 - BBQ

2011 - Trip to Anholt