Prof. Dr. Lena Burbulla recently successfully completed a project to research beta propeller protein-associated neurodegeneration (BPAN). The project, funded in 2019 with a total budget of € 65,000 by Aisnaf, NBIADA and Hoffnungsbaum e.V. jointly funded, was carried out at Northwestern University in Chicago over a period of 18 months.

BPAN is caused by mutations in the WDR45 gene, which is involved in autophagy, a mechanism by which unneeded components of our cells are broken down and recycled. To date, it is not clear how the mutation of the WDR45 gene leads to the accumulation of iron in the brain and all the disease features observed in patients with BPAN.

Defective lysosomes contribute to iron storage in neuronal cells.

In order to understand these mechanisms, the researcher first generated neurons from induced pluripotent stem cells (iPSCs) obtained from small skin flaps of patients. Examination of these neurons revealed that the WDR45 gene is probably involved in the process of autophagy, which ultimately leads to the degradation of proteins in the lysosomes. Lysosomes are organelles, or "small organs" within a cell, whose main function is to collect cellular waste and transport it out of the cell. The lysosomes in BPAN neurons are probably defective. They are therefore only able to dispose of proteins and cell organelles correctly to a limited extent. This could also affect iron-binding proteins. If this is confirmed in further studies, it could be a possible explanation for the pathological accumulation of iron observed in the neurons of BPAN patients. Examination of the neurons also revealed an accumulation of neuromelanin, which may be due to poor iron regulation. Neuromelanin is in fact one of the molecules that can bind iron and is typically present in dopaminergic neurons - the neurons most affected in BPAN. Prof. Burbulla's studies on the human BPAN model are promising preliminary findings, which will need to be further investigated in further studies.

Mini-brain as a three-dimensional disease model shows changes typical of BPAN

Another aim of the project was to create more sophisticated models of the disease, so-called mini-brains. Dr. Burbulla was able to create three-dimensional cellular structures from iPSCs of the patients. Of course, the human brain is much more complex than the mini-brains produced in the laboratory - and yet these allow the disease to be reproduced and studied in a "brain-like" system.

The analyses performed have confirmed that the mini-brains contain structures typical of the brain regions affected by BPAN and have revealed those pathological changes that are similar to those observed in simpler cellular models, such as the defects in the lysosomes and the accumulation of neuromelanin.

Research into therapeutic strategies for BPAN

A third part of the project was aimed at researching therapeutic strategies. Among the approaches tested, interesting preliminary results were obtained with antioxidant molecules that showed a partial improvement of the defects in the models. Ultimately, the results of the project, although still preliminary, open up new and interesting perspectives on the functions of the WDR45 gene with regard to the role it plays in neurons and with regard to possible new therapeutic strategies.

Prof. Lena Burbulla moves to Munich

After completing this project, Prof. Burbulla has since moved from Northwestern University in Chicago to the Biomedical Center at Ludwig-Maximilians-Universität in Munich, where she is leading the "oxDOPAMINE" project funded by the European Research Council as part of the SyNergy Cluster of Excellence. In this project, she wants to investigate why nerve cells in the midbrain are susceptible to an accumulation of the oxidized neurotransmitter dopamine and subsequently degenerate. As she suspects that, in addition to a defective dopamine metabolism, a disturbed iron balance also plays a critical role in this process, the researcher would also like to focus on rarer neurodegenerative diseases in addition to the relatively common Parkinson's disease. Research on BPAN will therefore also be part of her projects.

Hoffnungsbaum e.V. is very pleased that NBIA diseases will also play a role in Prof. Burbulla's future research projects, as they represent an ideal research model in view of the scientific issues surrounding impaired iron balance.

Editorial work: Angelika Klucken

Corrections: Prof. Lena Burbulla

Sources:
https://www.lmu.de/de/newsroom/news-und-events/news/sechs-neue-erc-grants-an-der-lmu.html
Lay Summary of the project: "Mechanistic insights into iron accumulation in WDR45 mutant neurons linked to β-propeller-associated neurodegeneration"