Systems Neurology (Behrends 1) 

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 roles of autophagy 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

Project description

De novo mutations in the gene encoding for the beta-propeller protein WIPI4 are causative for beta-propeller associated neurodegeneration (BPAN), an X-linked dominant human disorder characterized by iron accumulations in the brain. BPAN patients show early onset developmental delays with severe intellectual disability and rapid, progressive motor and cognitive regression in early adulthood. BPAN-linked mutations are thought to disrupt the beta-propeller structure resulting in a functional loss of WIPI4. WIPI4 is a phosphatidylinositol 3-phosphate binding protein whose function is best understood in the context of autophagy. Here, WIPI4 helps to tether PI3P-rich phagophores to adjacent ER or ER-derived membranes in complex with the lipid transfer protein ATG2A, ultimately leading to the expansion of phagophores into cup-shaped membranes that give rise to autophagosomes upon closure. WIPI4 knockout and BPAN patient-derived cells consistently exhibit compromised bulk autophagy, altered ER and mitochondrial morphology and proteostasis as well as an iron overload, suggesting defects in ferritinophagy, mitophagy, and ER-phagy, respectively. However, the molecular mechanisms that link WIPI4 function to ferritinophagy and possibly other selective autophagy pathways such as ER-phagy or mitophagy are still poorly understood. Furthermore, in order to firmly link WIPI4-dependent autophagy dysfunction to the onset of BPAN pathology, a systematic in-depth analysis of the role of WIPI4 in the autophagy pathway in brain cells is required. This project seeks to dissect the roles of WIPI4 in ferritinophagy and other types of selective autophagy and to determine brain-specific WIPI4 functions using newly established knockin mouse models. Overall, this project has the potential to advance our molecular understanding of WIPI4 function in selective autophagy and the causative role of WIPI4 mutations in BPAN.

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