Lena Burbulla discovers new possible BPAN disease mechanisms.

Prof. Dr. Lena Burbulla recently successfully completed a project investigating 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 conducted 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 to all the disease features observed in patients with BPAN.

Defective lysosomes contribute to iron storage in neuronal cells.

To understand these mechanisms, the researcher first generated neurons from induced pluripotent stem cells (iPSCs) derived from small skin flaps of patients. Examination of these neurons revealed that the WDR45 gene is likely involved in the process of autophagy, which ultimately leads to the degradation of proteins in 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 probably have defects. Therefore, they have a reduced ability to properly dispose of proteins and cell organelles. Among other things, 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 is likely 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 in the human BPAN model are promising preliminary findings, although they need to be explored in more detail in further studies.

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

Another goal 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 replicated 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 lysosomes and the accumulation of neuromelanin.

Exploring therapeutic strategies for BPAN

A third part of the project aimed at exploring therapeutic strategies. Among the approaches tested, interesting preliminary results were obtained with antioxidant molecules that showed partial improvement of the defects in the models. Ultimately, the results of the project, although still preliminary, open new and interesting perspectives on the functions of the WDR45 gene in terms of the role it plays in neurons and in terms of 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 neurons in the midbrain are susceptible to an accumulation of the oxidized neurotransmitter dopamine and subsequently degenerate. Since 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 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 in future research projects of Prof. Burbulla also NBIA diseases will play a role, which in view of the scientific questions around the disturbed iron balance represent an optimal research model for this.

Editorial: 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
Project Lay Summary: "Mechanistic insights into iron accumulation in WDR45 mutant neurons linked to β-propeller-associated neurodegeneration."