Objective: In this project, we are comprehensively studying the function of DJ-1 in PD and GBM to better understand its observed role in both, neurodegeneration and cancer.

Background: Mutations in the PD-associated gene PARK7 leading to loss of function of DJ-1 protein cause autosomal-recessive PD, whereas high levels of DJ-1 protein were found in different cancer types DJ-1 is also involved in GBM, a highly aggressive brain tumor that originates from astrocytes and that is associated with increased DJ-1 expression levels. As there is increasing evidence for a metabolic role of DJ-1, the focus is the involvement of DJ-1 in the impaired/increased glucose metabolism in neurodegeneration/cancer.

Method: To analyze the role of DJ-1 in the regulation of the metabolic switch of increased glycolysis in cancer and impaired metabolism in PD, stable isotope labeled glucose metabolite tracing was used. Metabolomics analysis was performed using human iPSC derived midbrain dopaminergic neurons, human iPSC derived astrocytes of an isogenic trio of wildtype, DJ-1 deficiency and DJ-1 overexpression and GBM cell lines. Astrocytes overexpressing DJ-1 serve as an oncogenic-like model to compare it to the GBM cell lines originating from astrocytes.

Results: In human iPSC derived midbrain dopaminergic neurons of the isogenic trio, 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. 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. In contrast, the loss of DJ-1 significantly reduces the glycolytic and TCA flux in astrocytes. The knockdown of DJ-1 reduces the glycolytic and TCA flux in GBM cells.

Conclusion: Our results show that the effect of DJ-1 on the metabolism in neurons, astrocytes and GBM cells is depending on its different protein levels. High levels of DJ-1 in GBM cells support, and low levels of DJ-1 in PD impair the metabolism. Based on the alterations in the glucose metabolism observed, we aim to identify the molecular target of DJ-1 that is responsible for these metabolic phenotypes in PD and GBM models.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/analyzing-the-metabolic-function-of-dj-1-in-the-pathogenesis-of-parkinsons-disease-pd-and-glioblastoma-multiforme-gbm/