Lena Burbulla discovers new possible BPAN disease mechanisms

from | August 2, 2021

Prof. Dr. Lena Burbulla recently successfully completed a project to investigate beta-propeller protein-associated neurodegeneration (BPAN). The project, 2019 with a total budget of €65,000 from Aisnaf, NBIADA and Hoffnungsbaum e.V. 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 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) obtained from small skin flaps of patients. From the study of these neurons, it emerged that the WDR45 gene is likely involved in the process of autophagy, which ultimately leads to the degradation of proteins in the lysosomes. Lysosomes are organelles, i.e. "small organs" within a cell, which have their main function in collecting cell waste and transporting it out of the cell. The lysosomes in BPAN neurons probably have defects. As a result, they are only able to dispose of proteins and cell organelles correctly to a lesser extent. This could also affect iron-binding proteins, among other things. If confirmed in further studies, it could be a possible explanation for the pathological accumulation of iron observed in the neurons of BPAN patients. The 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 by BPAN. Prof. Burbulla's studies on the human BPAN model are promising preliminary findings, but they still need to be investigated in more detail in further studies.


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

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 the patients' iPSCs. Of course, the human brain is much more complex than the lab-made mini-brains – and yet they allow the disease to be recreated and studied in a "brain-like" system.

The analyses carried out have confirmed that the mini-brains contain structures typical of the brain regions affected by BPAN and have revealed those pathological alterations 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, which showed a partial improvement of 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 in terms of the role it plays in neurons, as well as in terms of possible new therapeutic strategies.


Prof. Lena Burbulla moves to Munich

After completing this project, Prof. Burbulla moved from Northwestern University in Chicago to the Biomedical Center at the Ludwig-Maximilians-University in Munich, where she heads 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. Since she suspects that, in addition to a defective dopamine metabolism, a disturbed iron balance also plays a critical role, 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 their projects.

Hoffnungsbaum e.V. is very pleased that in future research projects of Prof. Burbulla, NBIA diseases will also play a role, which represent an optimal research model for this in view of the scientific questions surrounding the disturbed iron balance.


Editing: Angelika Klucken

Corrections: Prof. Lena Burbulla

Lay Summary of the project: "Mechanistic insights into iron accumulation in WDR45 mutant neurons linked to β-propeller-associated neurodegeneration"

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