Development of a human neuronal cell model of Beta-Propeller Protein-Associated Neurodegeneration (BPAN) as a drug screening platform
Robin Ketteler / London [UK]
BPAN is an X-linked subtype of Neurodegeneration with Brain Iron Accumulation (NBIA) caused by mutations in WDR45/WIPI4. The encoded beta-propeller protein has a postulated role in early stages of autophagy. The mechanisms linking autophagy, iron metabolism and neurodegeneration are poorly understood, and there are currently no available effective treatments. Here, we have developed a patient-derived, induced pluripotent stem cell (iPSc)-derived midbrain dopaminergic (mDA) neuronal model of BPAN to investigate disease mechanisms. Three patient-derived iPSc lines, two age-matched controls and two isogenic controls (generated via CRISPR/Cas9-mediated mutation correction in two BPAN lines) have been differentiated into mDA and extensively characterised. Furthermore, we developed a high-content autophagy assay in patient-derived ventral midbrain progenitors at Day 11 that is amenable to high-throughput screening. We have performed a drug screen using the FDA-approved Prestwick library and a series of novel autophagy activators. A number of compounds significantly correct an autophagy defect in all tested lines, and further validation is underway. In summary, our work in developing a mDA model of BPAN has provided an innovative platform for a) understanding pathophysiological mechanisms leading to striatonigral degeneration and b) performing imaging-based drug screening with the aim of identifying new treatments for this medically resistant condition.