Dynamic control of 26S proteasome function at CNS synapses (478.3)

Abstract

The selective strengthening and weakening of synapses in response to past experience and activity is known as synaptic plasticity and is fundamental to all brain processes such as the ability to learn, form memories and modify behavior. In contrast, impairments in synaptic plasticity are considered to contribute to neuropsychiatric disorders and neurodegenerative diseases. Synaptic plasticity is largely mediated by both morphological and functional modifications to synapses. Local protein synthesis and protein degradation are known to contribute to these modifications. It is now clear that regulated proteolysis via the ubiquitin proteasome system (UPS) plays a major role in the growth and development, maintenance and remodeling of synaptic connections in the brain. We and others have previously found a novel form of regulation for the 26S proteasome in neurons involving the plasticity kinase Ca2+/calmodulin‐dependent protein kinases II alpha (CaMKIIα). CaMKIIα phosphorylates the ATPase 19S regulatory particle (RP) subunit, Rpt6, at serine 120 (S120) in an activity‐dependent fashion to modulate the activity and control the distribution of proteasomes in neurons (Djakovic et al., 2009; 2012; Bingol et al., 2010). We find that Rpt6 phosphorylation and proteasome function regulates synaptic strength and activity‐dependent generation of dendritic spines (Djakovic et al., 2012; Hamilton et al., 2012). I will discuss our more recent work and the functional relevance of proteasome phosphorylation in neurons using newly generated Rpt6 Ser120Ala and Ser120Asp (phospho‐dead and phospho‐mimetic, respectively) genetically modified mice.