Pauline MENCKE

Analyzing the role and function of DJ-1 in Parkinson`s disease (PD) and Glioblastoma multiforme (GBM)

Objectives
In this project, we are simultaneously studying the role and function of DJ-1 in PD and GBM to better understand its role in both conditions.
Background
Mutations in the PD-associated gene PARK7 leading to loss of function of DJ-1 protein cause autosomal-recessive PD. DJ-1 is also involved in GBM, a highly aggressive brain tumor that originates from astrocytes and that is associated with high DJ-1 expression levels.
Methods
To analyze the role of DJ-1 in the regulation of the metabolic switch in cancer and PD, stable isotope labeled glucose metabolite tracing was used.
Results
In iPSC derived midbrain dopaminergic neurons of an isogenic trio of wildtype, DJ-1 deficiency (PD-associated DJ-1 mutation) and DJ-1 overexpression, glucose tracing showed a significantly increased glycolytic and TCA flux in the DJ-1 overexpression line and a decreased TCA flux in the DJ-1 deficient line. Concordant with the increased TCA flux, we found a significantly increased abundance of pyruvate dehydrogenase in DJ-1 overexpression neurons. In contrast, glucose tracing in astrocytes of the isogenic trio and a second PD-patient iPSC derived isogenic pair carrying a DJ-1 mutation revealed that overexpression of wildtype DJ-1 increases the glycolytic and TCA flux and that the loss of DJ-1 significantly reduces the glycolytic and TCA flux. Consistent with these findings, we observed that the knockdown of DJ-1 reduces the glycolytic and TCA flux in GBM cells.
Conclusion
Based on the metabolic alterations observed, we aim to identify a target of DJ-1 that is responsible for these metabolic phenotypes in PD and GBM models.

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