Integrative analysis of peripheral N-acetylaspartate metabolism

Canavan disease (CD) is a rare leukodystrophy caused by mutations in the ASPA gene, leading to severe neurodegeneration and short life expectancy. To date, the exact disease mechanism is poorly understood and therapeutic options are scarce. The ASPA gene encodes aspartoacylase, an enzyme catalyzing the degradation of N-acetylaspartate (NAA). Despite NAA being the second-most abundant metabolite in the mammalian brain, its functional role is poorly understood. Recently, several independent groups found NAA metabolism to also play important roles in non-nervous tissues, e.g. in adipocytes, immune cells, lung and prostate cancer cells, pointing towards a previously overlooked wide relevance of peripheral NAA metabolism.

In the PeriNAA junior research alliance, clinical, experimental and computational groups are collaborating to generate a computational model around NAA metabolism and inferring model parameters from stable isotope-assisted metabolomics data, RNA-seq data, and other experimental data. We will use this model to iteratively generate and test various hypotheses around NAA metabolism and its function in cellular metabolism. Thereby, we expect to obtain a more profound understanding of the roles of NAA in metabolism and signaling, particularly in cells outside the brain, which is relevant for understanding and treatment of CD and other diseases. Based on these findings we will generate predictions of possible drug targets or intervention points for CD treatment other than NAT8L or ASPA which we will validate in vitro and potentially in vivo. Additionally, we will develop and apply a novel disease severity classification system for CD patients based on clinical abilities and radiological criteria, which we will try to link to molecular data.