The goal of Burbulla, a professor at Northwestern University of Chicago (Illinois, USA), is to define the mechanisms that lead to the emergence and progression of BPAN, with a focus on the role of iron in the disease. All of this is based on solid preliminary data showing how the loss of function of the protein WIPI4/WDR45, mutated in BPAN patients, causes cells to be unable to break down iron-containing macromolecules and organelles, reducing their recycling.
Iron is an essential element of cellular life, but its levels need to be fine-tuned, as "free" iron is highly reactive and can be potentially destructive. "When it enters the cells, iron is incorporated into the mitochondria, the cellular power plants, or stored by special proteins called ferritins. Mitochondria and ferritins are therefore the iron-rich cellular macromolecules: they can be degraded by autophagy and release iron, which thus becomes bioavailable," explains Burbulla. The scientist's innovative hypothesis is based on the idea that the disease formation of BPAN is not so much due to an accumulation of iron, but to a deficit of bioavailable iron, which cells need for their proper functioning. To test this hypothesis, Burbulla has planned a series of experiments on neurons made from the so-called induced pluripotent stem cells (iPSCs), which are obtained from small skin samples from BPAN patients. The advantage of this technique is that the causes of the disease can be detected directly in the diseased cells, but without invasive interventions. Once the mechanisms that cause the accumulation of non-usable iron on the one hand and the lack of bioavailable iron on the other have been identified, Burbulla's team of researchers want to test new therapeutic approaches, using innovative technologies such as three-dimensional brain organoids that mimic in the laboratory what happens in the areas of the brain that are most affected in BPAN patients.
This study will lay the groundwork for the identification of potential therapeutic targets for the future development of a cure for BPAN. However, it will also be important to improve our understanding of the link between iron and neurodegeneration, which can also be applied to other forms of NBIA.