SP 2 - PeriNAA
(Patho-)Metabolism of N-acetylaspartate
Canavan disease (CD) is an inborn error of metabolism that leads to a pathological accumulation of N-acetylaspartate in the brain due to a deficiency of the enzyme aspartoacylase. This is accompanied by severe neurodegeneration, developmental disabilities, and a short life expectancy. To date, the exact disease mechanisms are poorly understood and CD is considered incurable. One of the reasons for a lack of therapies is that the functional role of N-acetylaspartate in metabolism is largely unknown. It has long been assumed that N-acetylaspartate is a brain specific metabolite. However, there is increasing evidence that N-acetylaspartate metabolism also plays an important role in peripheral organs, for example in adipose tissue, in immune cells and in lung and prostate cancer cells. For example, we recently showed that N-acetylaspartate plays an important role in the proliferation of cancer cells. Since cancer cells usually hijack/adoptevolutionary conserved cellular mechanisms, we hypothesize that the basic function of N-acetylaspartate in cancer metabolism is similar to that in the brain. For this reason, this subproject first aims to understand the functional role of N-acetylaspartate in cancer cell metabolism, and then to subsequently transfer it to Canavan mouse models and finally to Canavan patients (Figure 1). To reach our aims, we will apply modern cell biology methods, high-resolution mass spectrometry in combination with stable isotope-based methods, and high-throughput sequencing. The resulting data then forms the basis for the dynamic computer model of N-acetylaspartate metabolism developed in subproject 3. Through this system-medical approach, we hope to find potential treatment options for Canavan disease, but also aim to increase our understanding of N-acetylaspartate metabolism in general, especially the significance outside the brain.