Understanding beta-propeller protein-associated neurodegeneration using stem cell models

Summary Understanding beta-propeller protein-associated neurodegeneration using stem cell models

Project Details

Beta-propeller Protein-Associated Neurodegeneration (BPAN) is a rare, X-linked neurological disorder characterised by intellectual disability, seizures and ataxia in early childhood. The condition progresses rapidly leading to development of Parkinsonism, dystonia and cognitive impairment in adolescence/early adulthood. Children affected by BPAN display brain iron accumulation at an early age, leading to classification of BPAN under a group of disorders known as neurodegeneration with brain iron accumulation (NBIA5).

BPAN is caused by pathogenic variants in the WDR45 gene which encodes the WD repeat-containing protein 45. The protein plays an important role in autophagy, a biochemical mechanism that regulates degradation and recycling of cellular components. However, very little is known about the cellular effects of variants in WDR45 on the nervous system and how it causes BPAN. Hence, there are no drugs available that can cure or slow the progression of BPAN.

In this project we use patient-derived induced pluripotent stem cells (iPSC) to generate brain cell cultures in order study disease-specific mechanisms and test potential drug treatments. The first step will be to examine the effects of pathogenic variants on electrophysiological, biochemical and morphological properties of differentiated cells, with a focus on neurons. Drugs targeting relevant pathways (e.g. autophagy, iron metabolism, etc.) will then be tested to determine their effectiveness in modulating disease phenotypes in neurons. This project aims to establish the iPSC model as a vital preclinical tool for BPAN drug screening prior to initiation of clinical trials. The prospective candidate will get the opportunity to learn a range of laboratory techniques including stem cell culturing, differentiation of stem cells into neurons, electrophysiology, immunocytochemistry, microscopy, drug screening assays, real-time qPCR and western blot analysis.