Pharmacology and Molecular Biology
Our group is interested in the analysis of cation channels of the TRP (transient receptor potential) superfamily within the trafficking network of the endolysosomal system. Lysosomes are cell organelles involved in the breakdown of proteins, lipids, and other macromolecules. Lysosomal dysfunction can result in endolysosomal storage disorders (LSDs) such as mucolipidoses or mucopolysaccharidoses but is also implicated in metabolic diseases, the development of neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease, retinal diseases and pigmentation disorders, trace metal deficiencies such as iron deficiency, and even cancer. Highly critical for the proper function of lysosomes, endosomes, and lysosome-related organelles (LROs) is the tight regulation of various fusion and fission processes and the regulation of proton and other cation concentrations within the endolysosomal system (ES). TRPML cation channels (TRPML1, 2 and 3) and Two-pore channels (TPCs) have recently emerged as important regulators of such processes within the ES and appear to be essential for a proper communication between the various endolysosomal vesicles. We use lysosomal patch-clamp techniques, molecular and cell biology techniques as well as knockout mouse models to study the physiological roles and activation mechanisms of these ion channels in-depth.
Fig.1, The endolysosomal system (ES) as it is found in almost every cell of the human body, typically consists of early endosomes (EE), recycling endosomes (RE), multi-vesicular bodies (MVB), late endosomes (LE), and lysosomes (LY). The ES is required for the intracellular transport, recycling and degradation of receptors and other macromolecules as well as trace metals such as iron and lipids. Dysfunction of this intracellular trafficking machinery can lead to lysosomal storage disorders (LSDs), pigmentation disorders, metabolic diseases, the aggravation of infectious diseases, retinal diseases e.g. due to dysfunction of the retinal pigment epithelium (RPE) and plays important roles in the development of cancer and neurodegenerative diseases such as Alzheimer’s or Parkinson’s disease. TRPML channels and TPCs have recently emerged as important regulators of trafficking and fusion processes within the ES and appear to be essential for a proper communication between the various endolysosomal vesicles. Rab5 = marker for EE, Rab11 = marker for RE, Rab7 = marker for LE.