PP2A B' subunit regulates synaptic development and cognition - learning fromhuman mutations

PP2A B’ subunit regulates synaptic development and cognition — learning from human mutations Abstract Intellectual disability (ID) is a severe neurological condition affecting up to 3% of the general population. There is currently no pharmacological treatment for ID patients. Gene-association studies in ID patients identified an increasing number of genes. However, a vast gap persists between gene discovery and treatment due to our poor understanding of the molecular mechanisms linking cognition and genes. Two ID-linked genes are PPP2R5C and PPP2R5D, both encoding brain-enriched B56 regulatory subunits of the PP2A phosphatase complex. However, it is unclear how the ID-linked mutations in PPP2R5C or PPP2R5D affect the B56 subunit action and subsequent cognitive function. Our studies on wrd, the sole fly orthologue of both PPP2R5C and PPP2R5D, shed light on how these specific subunits of PP2A phosphatases regulate synaptic development, neural-activity-driven synaptic structural remodeling, learning and memory. We found that Wrd-PP2A mediates dephosphorylation events crucial for structural plasticity at the nerve terminals. Loss of wrd function destabilizes active zones at the larval glutamatergic neuromuscular junctions, diminishes light-induced remodeling of active zones at the photoreceptor synapses, and impairs gustatory learning in the adult stage. Transiently expressing Wrd protein in adulthood restores the gustatory learning defect in the wrd null mutant flies. These findings together suggest an exciting potential for boosting Wrd-PP2A activity (or inhibiting antagonizing kinases of Wrd-PP2A) as a treatment for ID. In this grant, we propose to generate and study fly Wrd transgenes that mimic the ID-linked mutations in human patients. Our study will establish a fly model to dissect the molecular mechanisms underlying the root causes of B56-dependent cognitive dysfunctions, paving the road for future therapeutic approaches in treating B56-linked and other forms of ID.