PPP2R5D-related neurodevelopmental disorders: pathologic mechanisms and therapeutic avenues

Reversible protein phosphorylation is a majorly important post-translational modification involved in cell regulation and signaling. Dysfunctions of the kinases or phosphatases involved often result in human pathologies, including cancer, diabetes, immunologic and neurologic disorders. For more than 20 years, we have studied in our lab, the structure, function and regulation of Protein Phosphatase 2A (PP2A), the major family of Ser/Thr-specific phosphatases in most cells and tissues. In 2015, we discovered that inborn, de novo mutations in specific PP2A genes are the cause of a new genetic disorder, characterized by intellectual disability, (neuro)developmental delay, hypotonia, dysmorphic features, and sometimes epilepsy, autism, heart defects and brain abnormalities (Houge*,Haesen* et al. 2015; Reynhout*, Jansen* et al. 2019). Biochemical characterization of the variants revealed these mutations predominantly result in PP2A losses-of-function, although potential gains-of-function might not be excluded at this point. While PP2A shows high expression in brain and regulates a broad network of neuronal signaling cascades, it is currently not known which specific pathways are affected by these genetic PP2A alterations, or which brain areas might be dysfunctional. The aim of this project is to phenotypically characterize in depth different in vitro and in vivo models of this syndrome, including a neuronal cell model derived from human patient-derived iPCSs and a mouse model, in which the most recurrent PP2A mutation was introduced. These studies, coupled to extended biochemical assays to better understand the consequences of the mutation at the PP2A enzyme level, will provide the first patho-physiological insights into this new genetic disorder. These insights should eventually allow us to guide new therapeutic approaches to treat this disease and improve the general health of affected individuals.