- Department / Institute
- Munich Cluster for Systems Neurology (SyNergy)
- Subject area
- Biochemistry, Cell Biology, Proteomics, Disease Mouse Models
- Name of supervisor
- Prof. Dr. Christian Behrends
- Number of open positions
- Project title
- Exploring the role of TECPR2 in neurodegeneration
- Language requirements
- Fluency in English
- Academic requirements
- 4-year Bachelor's plus Master's degree; excellent technical skills, an enthusiasm for using and developing new techniques, and the interpersonal ability to work within a diverse team of scientists; experience with mouse experiments is preferred.
- Study model
- Full doctoral study model: 48 months
Hereditary sensory and autonomic neuropathy 9 (HSAN9) is a rare fatal neurological disease caused by mis- and nonsense mutations in the gene encoding for Tectonin β-propeller repeat containing protein 2 (TECPR2). While we previously found that TECPR2 is required for lysosomal consumption of autophagosomes (Fraiberg et al. 2021) and ER-to-Golgi transport (Stadel et al. 2015), it remains elusive how exactly TECPR2 is involved in autophagy and secretion and what downstream sequels arise from defective TECPR2 due to its involvement in these processes. Recently, we addressed these questions by determining which proteins depend on TECPR2 for their trafficking out of the ER and sorting within the cell. Thereto, we employed a series of spatial proteomic approaches to systematically examine defects along the secretory pathway in an HSAN9-mimicking cell model. In addition, we identified a number of ER- and Golgi-associated TECPR2 binding partners whose interactions are lost when TECPR2’s C-terminus is missing due to pathogenic mutations, thus supporting a loss-of-function mechanism for HSAN9 (Nalbach et al. 2023). However, so far, mechanistic insights into how TECPR2 coordinates its association with components of the different trafficking and sorting machineries remained unclear. Hence, key elements which might help to understand TECPR2’s molecular function are not fully understood. To close this critical knowledge gap, this project focuses on the molecular dissection of TECPR2 with the aim to determine critical interaction sites with partner proteins and cellular membranes which may coordinate the involvement of TECPR2 in trafficking and protein sorting. To do so, we will combine a range of biochemical and cell biological techniques with innovative proteomic approaches and a newly established HSAN9 mouse model. The expected results will yield mechanistic insights into the biochemical and cellular role of TECPR2 and deepen our understanding of the molecular consequences of TECPR2 deficiency. Both aspects have the potential to contribute to rationalizing strategies to rescue or bypass TECPR2 malfunction which is urgently needed to develop treatment options for HSAN9 patients.