The E3 ubiquitin ligase IDOL regulates synaptic ApoER2 levels and is important for plasticity and learning

Abstract

Neuronal ApoE receptors are linked to learning and memory, but the pathways governing their abundance, and the mechanisms by which they affect the function of neural circuits are incompletely understood. Here we demonstrate that the E3 ubiquitin ligase IDOL determines synaptic ApoER2 protein levels in response to neuronal activation and regulates dendritic spine morphogenesis and plasticity. IDOL-dependent changes in ApoER2 abundance modulate dendritic filopodia initiation and synapse maturation. Loss of IDOL in neurons results in constitutive overexpression of ApoER2 and is associated with impaired activity-dependent structural remodeling of spines and defective LTP in primary neuron cultures and hippocampal slices. IDOL-deficient mice show profound impairment in experience-dependent reorganization of synaptic circuits in the barrel cortex, as well as diminished spatial and associative learning. These results identify control of lipoprotein receptor abundance by IDOL as a post-transcriptional mechanism underlying the structural and functional plasticity of synapses and neural circuits.

Inactivation of the E3 Ubiquitin Ligase IDOL Attenuates Diet-Induced Obesity and Metabolic Dysfunction in Mice

“…Although Idol expression is ubiquitous, 11 it is highly expressed in neurons, controls its targets in these cells, and can influence cognitive function in mice. 13 , 15 , 32 Although we cannot evaluate the impact of the idol neuronal effects in our experimental setting, our analysis of the BXD cohorts shows that hepatic Idol expression correlates with several of the metabolic parameters affected in the global Idol-KO mice. Clearly, development of tissue-specific Idol-KO models will be required to obtain a more precise view of the role of Idol in metabolism.…”

IDOL regulates systemic energy balance through control of neuronal VLDLR expression

“…Having ruled out the peripheral metabolic tissues as the source of the IDOL-VLDLR effect on energy balance, we considered the CNS as a potential site of action. Prior studies showed that the IDOL pathway in the CNS affects the function of both microglia and neurons 29,30 ; however, the possibility that central actions of IDOL affect metabolism has not been addressed. To test whether IDOL was acting centrally, we developed a CNS-optimized antisense oligonucleotide (ASO) targeting Idol.…”

Regulation of intestinal LDLR by the LXR-IDOL axis

“…Idol is an LXR-regulated E3 ubiquitin ligase that promotes the ubiquitylation and subsequent degradation of the LDLR and its related family members, the very low density lipoprotein receptor and ApoE receptor 2 [26,27]. In line with the regulation of these receptors, we and others have shown that Idol plays a prominent role in a wide range of (patho)physiological conditions, including regulation of systemic lipid and energy metabolism [28][29][30], Alzheimer's disease [31], neuronal function [32,33] and viral entry [34], as reviewed in [35]. Moreover, genetic variation in the IDOL locus has been associated with circulating cholesterol levels in humans [36], and we and others have reported IDOL variants that influence cholesterol levels in human carriers [37][38][39].…”