Lysosomes are cell organelles involved in the breakdown of proteins, lipids, and other molecules and have been implicated not only in endolysosomal storage disorders (LSDs) such as mucolipidoses or mucopolysaccharidoses but also in metabolic diseases, neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease, pigmentation disorders, or infectious diseases. Highly critical for the proper function of lysosomes, endosomes, and lysosome-related organelles is the tight regulation of various fusion and fission processes and the regulation of proton and other ionic concentrations within the endolysosomal system. Calcium permeable, non-selective cation channels of the TRP (transient receptor potential) superfamily, namely TRPML channels (mucolipins) and TPCs (two-pore channels) have been found to play important roles in these processes. This thesis provides insights into the function and physiology of TRPML and TPC channels, explains the molecular basis of pathologies associated with diseases caused by loss or mutation of these channels, and discusses potential therapeutic approaches.
Table of contents
1 List of original publications selected for this „Habilitationsschrift“
2 Introduction
3 Analysis of the TRPML3 varitint-waddler mouse mutants
4 Development of small molecule agonists for TRPML channels
5 Functional investigation of MLIV causing TRPML1 mutants
6 Novel TRPML channel interaction partners
7 Functional analysis of the TPC2-/- knockout mouse
8 Novel TPC channel interaction partners
9 Summary
10 References
11 Curiculum vitae
12 Complete list of original publications
13 Personal contributions to the selected original publications
14 Acknowledgement
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