Volker Haucke

Cells communicate with each other by secreting signaling molecules and recognizing those from other cells. For example, nerve cells release neurotransmitters contained in small membrane-bounded vesicles at synaptic cell contacts to elicit responses in neighburing cells. We are studying how nerve cells form and assemble synapses and how synaptic vesicles containing messenger substances are recycled to keep synapses up to speed in fractions of a second. If these processes are disrupted, neurological and neurodegenerative diseases such as Alzheimer’s disease may occur. Not only neurons, but almost all cells in our body release or respond to signaling molecules. Growth factors such as insulin and nutrients promote cell growth and division, while suppressing the degradation of metabolites. In cancer cells, this nutrient signaling pathway is often disturbed. We have deciphered cellular mechanisms that regulate nutrient signaling and thus the balance between cell growth and metabolite degradation. Understanding these mechanisms is essential for a better understanding of diseases such as cancer and diabetes. In addition, we use this knowledge to develop new pharmacological approaches for the treatment of such diseases.

In the Haucke laboratory we aim to understand cellular communication in health and disease at the level of membrane-enclosed compartments that dynamically exchange materials between them. Our main focus is on the analysis of the endocytic and endolysosomal systems in genome-engineered cells and in nerve tissue. The laboratory uses a broad range of techniques including biochemical and molecular biology approaches, super-resolution light and electron microscopy, chemical biology and screening technology, electrophysiology as well as genetic and genome engineering in cell-based models and in vivo.
The overarching goal of our research is to understand the basic principles that enable proteins and lipids to control membrane flux within cells and, thereby, regulate cell and tissue function with a focus on the nervous system. We use this know-how to develop novel strategies for pharmacological or genetic interference that can pave the way to cure diseases including epilepsy, neurodegeneration, lysosomal disorders, myopathies, and cancer.

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• Discovery of a lipid-controlled organellar relay centered around MTM1, a phosphoinositide 3-phosphatase mutated in X-linked centronuclear myopathy in humans, that transmits nutrient-triggered changs in endosomal signaling lipid levels to mitochondria to enable metabolic rewiring (Jang et al., Science 2022).
• Phosphatidylinositol 3,4-bisphosphate [PI(3,4)P₂] synthesized by phosphatidylinositol-3-kinase C2α (PI3KC2α) is a novel key lipid that spatiotemporally controls endocytosis (Posor et al., Nature 2013;  Wang et al., Mol. Cell 2018; Lo et al., Nat. Struct. Mol. Biol. 2022). Newly developed highly selective inhibitors of PI3KC2α impair endocytic membrane dynamics and display anti-thrombotic activity (Lo et al., Nat. Chem. Biol. 2022)
• Membrane retrieval at synapses (Haucke et al., Nat. Rev. Neurosci. 2011) occurs in part by clathrin-independent endocytosis, while clathrin and its major endocytic adaptor AP-2 regenerate synaptic vesicles from internal endosome-like vacuoles in addition to their action at the plasma membrane (Kononenko et al., Neuron 2014; Lopez-Hernandez et al., eLife 2022). Clathrin-independent endocytosis of synaptic vesicles is driven by formin-dependent actin assembly (Soykan et al., Neuron 2017).
• Identification of the kinesin adaptor Arl8 as a conserved factor required for delivery of presynaptic components during neuron development (Vukoja et al., Neuron 2018).
• Identification of phosphatidylinositol-3-kinase C2β (PI3KC2β) as a negative regulator of mTorc1 signaling under the control of protein kinase N (Marat et al., Science 2017; Wallroth et al., Nature Cell Biol. 2019). Mutations in PI3KC2β cause focal epilepsy in humans (Gozzelino et al., Brain 2022).
• Defective phosphoinositide conversion at endosomes underlies X-linked centronuclear myopathy (Ketel et al., Nature 2016).

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