Project number 25

Role of the vacuolar protein sorting gene VPS13C in the pathogenesis of frontotemporal dementia

Promotors: Wim Annaert (wim.annaert*Replace*With*At*Sign* ), and Christine Van Broeckhoven (christine.vanbroeckhoven*Replace*With*At*Sign* ), VIB
Frontotemporal dementia (FTD) is a heterogeneous group of neurodegenerative brain diseases characterized by cerebral atrophy. Recently, the group of C. Van Broeckhoven identified mutations in the vacuolar protein sorting 13 homolog C (VPS13C) (Philtjens et al., submitted). Studies on orthologous VPS13 proteins indicate essential roles in transport between the Golgi, lysosomes and the plasma membrane. We aim here to explicate the role of VPS13C in neuronal transport required to understand the effects of FTD-linked mutations.
Additional Belgian FTD patients and relatives will be screened for mutations in VPS13C and carriers approached for their obtaining fibroblasts to generate IPS cells, or alternatively, from available lymphoblasts. Genetic studies will identify potential genetic modifier effects on disease onset and progression by the presence of genetic variants in known FTD genes as well as FTD risk genes. (Preclinical) VPS13C carriers will be included in clinical follow-up studies.
In the group of W. Annaert, known mutations in VPS13C will be introduced in neuronal progenitor cells (NPCs) using CRISPR/Cas9 and used for deriving human neuronal models of FTD mutations. These together with VPS13C deficient and rescued differentiated NPCs will be a starting point for functional studies. Analyses will be focused on autophagy/lysosomal biology, golgi-to-endosome transport and organellar contact sites and includes in vitro transport assays and state-of-the-art imaging (Sannerud et al., 2016). New functional insights will be validated in neurons differentiated from control and patient-derived IPS cells.
Understanding the role of VPS13C in FTD might result in new avenues for treatment. Today, there are no disease modifying or curing medications or treatments for FTD.

frontotemporal dementia, VPS13C, IPS cells, differentiated neurons, membrane transport regulation

Wim Annaert, VIB Center for the Biology of Disease, KU Leuven, Leuven
Christine Van Broeckhoven, VIB Dept. of Molecular Genetics, University of Antwerp, Antwerp