Willnow Lab

Willnow Lab

Molecular Cardiovascular Research

Profile

Age-related dementias, as in Alzheimer disease, are a global health problem of epidemic proportions. Disturbingly, disorders of the metabolism, such as obesity or diabetes, represent major risk factors for Alzheimer disease, causally linking the most common illnesses inflicting our societies.

We study genes associated with both metabolic disorders and Alzheimer’s disease, aiming to provide explanatory models for metabolic dysfunctions as major cause of neurodegeneration. We elucidate gene functions using humanized mouse models and validate the clinical relevance of our findings in studies involving patients and iPSC models thereof. In this reporting period, we focused on a class of intracellular sorting receptors, called VPS10P domain receptors, identifying essential roles for directed protein transport in control of cell viability and function common to metabolic and brain cell types. We uncovered molecular mechanisms whereby receptor (dys)functions cause rare familial but also common sporadic disorders of the metabolism and the ageing brain, paving the way for therapeutic strategies to combat age-related dementia - devastating conditions impacting millions of patients worldwide.

Team

Research

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.

 

Publications

News

Fun Stuff

2015 - Hiddensee

2013 - Climb-up

2012 - BBQ

2011 - Trip to Anholt

Portrait
Prof. Dr. Thomas Willnow
Group Leader
Contact
Max-Delbrück-Centrum für Molekulare Medizin (MDC)
Robert-Rössle-Str. 10
13092 Berlin, Germany
 
Secretariat
 
Verona Kuhle
(030) 9406 2387
Building 27: Walter-Friedrich House, Room 114