Finding memo: versatile interactions of the VPS10p-Domain receptors in Alzheimer’s disease

Abstract

The family of VPS10p-Domain (D) receptors comprises five members named SorLA, Sortilin, SorCS1, SorCS2 and SorCS3. While their physiological roles remain incompletely resolved, they have been recognized for their signaling engagements and trafficking abilities, navigating a number of molecules between endosome, Golgi compartments, and the cell surface. Strikingly, recent studies connected all the VPS10p-D receptors to Alzheimer’s disease (AD) development. In addition, they have been also associated with diseases comorbid with AD such as diabetes mellitus and major depressive disorder. This systematic review elaborates on genetic, functional, and mechanistic insights into how dysfunction in VPS10p-D receptors may contribute to AD etiology, AD onset diversity, and AD comorbidities. Starting with their functions in controlling cellular trafficking of amyloid precursor protein and the metabolism of the amyloid beta peptide, we present and exemplify how these receptors, despite being structurally similar, regulate various and distinct cellular events involved in AD. This includes a plethora of signaling crosstalks that impact on neuronal survival, neuronal wiring, neuronal polarity, and synaptic plasticity. Signaling activities of the VPS10p-D receptors are especially linked, but not limited to, the regulation of neuronal fitness and apoptosis via their physical interaction with pro- and mature neurotrophins and their receptors. By compiling the functional versatility of VPS10p-D receptors and their interactions with AD-related pathways, we aim to further propel the AD research towards VPS10p-D receptor family, knowledge that may lead to new diagnostic markers and therapeutic strategies for AD patients.

Internally tagged Vps10p-domain receptors reveal uptake of the neurotrophin BDNF

“…Notably, the variant SorCS1b is the only Vps10p-D receptor lacking a functional internalization motif in its cytoplasmic domain and is localized predominantly to the cell surface ( 33 ). In contrast, all other SorCS1 splice variants, such as the here studied SorCS1c-α, and all other Vps10p-D receptors are endocytic receptors targeted mainly to Golgi and endosomal compartments ( 1 , 26 , 27 ).…”

“…Sorting receptors of the Vps10p-D family play a role in endosomal targeting, secretion, and internalization of soluble ligands. In addition, they govern also the subcellular localization of other proteins, but the underlying molecular determinants are incompletely understood ( 1 , 26 , 27 ). Deciphering the localization and mobility of Vps10p-D receptors inside a cell and directly observing their interactions at spatial and temporal levels to examine local dynamics by live imaging has been challenging.…”

“…Because of the intracellular sorting function of yeast Vps10p, sorting properties were also proposed for the mammalian Vps10p-D receptors. In agreement, these bind different ligands and mediate their secretion, internalization, and sorting through the endosomal system ( 1 , 26 , 27 ). All family members present a large luminal/extracellular moiety followed by a transmembrane domain and a short cytoplasmic tail ( Fig.…”

Spatial transcriptomic analysis of the mouse brain following chronic social defeat stress

“…[ 80 , 81 ] It is associated with the behavioural phenotype of depression, AD and other psychiatric disorders. [ 82 ] Sorcs3‐deficient mice showed deficits in hippocampal LTD behaviour, especially in the accelerated extinction of fear memory. [ 81 ] Therefore, Ngf/Sorcs3 may play a potential role in CSDS‐induced synaptic dysfunction in mice.…”

SORCS2 activity in pancreatic α-cells safeguards insulin granule formation and release from glucose-stressed β-cells

“…Early studies have mainly focused on functions of VPS10P domain receptors in neuronal protein trafficking, providing molecular explanations for their causal roles in psychiatric and neurodegenerative diseases (reviewed in 1 , 2 ). Surprisingly, recent work now uncovered genetic association of these receptors with metabolic traits in humans and mouse models, including obesity, 3 hypercholesterolemia, 4 , 5 , 6 and type 2 diabetes (T2D).…”