Port‐to‐port delivery: Mobilization of toxic sphingolipids via extracellular vesicles

Abstract

The discovery that most cells produce extracellular vesicles (EVs) and release them in the extracellular milieu has spurred the idea that these membranous cargoes spread pathogenic mechanisms. In the brain, EVs may have multifold and important physiological functions, from deregulating synaptic activity, to promoting demyelination, to changes in microglial activity. The finding that small EVs (exosomes) contain α-synuclein and β-amyloid, among other pathogenic proteins, is an example of this notion, underlining their potential role in the brain of patients with Parkinson’s and Alzheimer’s diseases. Being membranous-vesicles, we speculate that EVs also have an intrinsic capacity to incorporate sphingolipids. In conditions where these lipids are elevated to toxic levels such as in Krabbe’s disease and Metachromatic leukodystrophy, EVs may contribute to spread disease from sick to healthy cells. In this essay, we discuss a working hypothesis that brain cells in sphingolipidoses clear some of the accumulated lipid material to attempt restoring cell homeostasis via EV secretion. We hypothesize that secreted sphingolipid-loaded EVs shuttle pathogenic lipids to cells that are not intrinsically affected, contributing to establishing non-cell autonomous defects.

Exosomes: Revisiting their role as “garbage bags”

“…Although caused by mutations in either of the genes of NPC1 or NPC2 proteins involved in cholesterol transport out of lysosomes, Niemann‐Pick type C disease also leads to sphingolipids accumulation in late endosomes/lysosomes. Toxic sphingolipids such as sulfatides or psychosine have been shown to accumulate in some sphingolipidoses and to be secreted with EVs . The cellular ceramide content has also been shown to be regulated by exosome secretion through adiponectin binding to T‐cadherin .…”

“…Toxic sphingolipids such as sulfatides or psychosine have been shown to accumulate in some sphingolipidoses and to be secreted with EVs. 118,119 The cellular ceramide content has also been shown to be regulated by exosome secretion through adiponectin binding to Tcadherin. 120 Adiponectin is a protein secreted by adipocytes as oligomers that bind to T-cadherin, a unique GPI-anchored form of cadherin notably present in lipid rafts of endothelial vascular cells.…”

A Targeted Mass Spectrometric Analysis Reveals the Presence of a Reduced but Dynamic Sphingolipid Metabolic Pathway in an Ancient Protozoan, Giardia lamblia

“…Evidence shows that SLs and GSLs secreted by eukaryotic cells play an important role in maintaining cellular functions, cellular communications, and microbe-host cell interactions. In the case of sphingolipidosis (a pathogenic neuronal condition), brain cells release toxic SLs through exocytic vesicles to restore normal cellular functions (Scesa et al, 2016). Likewise, the white-rot fungus, Ceriporiopsis subvermispora , which degrades lignin, was shown to release cerebrosides to communicate with the surrounding microbial community (Nishimura et al, 2017).…”

Fluid levity of the cell: Role of membrane lipid architecture in genetic sphingolipidoses

“…For Krabbe's disease, our group reported in vivo axonal swelling in spinal cords and peripheral nerves of twitcher mice and also in cultured mutant neurons and motoneurons incubated with psychosine (Castelvetri et al, ). In sphingolipidoses, in which there is a progressive accumulation of SLs in the membrane, increased bending could lead to exacerbated shedding of the membrane, an emerging mechanism with significant roles in pathophysiology (Herring et al, ; see also Scesa et al, ). Altogether these data underscore the activation of common pathological changes of membranes, including increased rigidity, bending, swelling, and vesiculation, promoted by the presence of SLs (Fig.…”