Regulation of PP2Ac stability – discovery of a novel α4 monoubiquitination-dependent mechanism that is altered in Alzheimer’s disease

Abstract

Studies described in this thesis identify a novel mechanism for α4’s regulation of PP2Ac stability. α4 binds the PP2A catalytic subunit (PP2Ac) and the microtubule-associated E3 ubiquitin ligase MID1, and through unknown mechanisms can both reduce and enhance PP2Ac stability. We show MID1-dependent monoubiquitination of α4 triggers calpain-mediated cleavage at the F255-G256 bond in α4 releasing α4 from MID1. The cleavage of α4 switches its activity from protective to destructive towards PP2A, and results in the increase in phosphorylation of the microtubule-associated protein (MAP) tau. This regulatory mechanism appears important in MAP-dependent pathologies as levels of cleaved α4 are decreased in Opitz Syndrome (OS) and increased in Alzheimer’s disease (AD), disorders characterized by MAP hypophosphorylation and hyperphosphorylation, respectively. These findings indicate that regulated inter-domain cleavage controls the dual functions of α4, and dysregulation of α4 cleavage may contribute to OS and AD.