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

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, underscoring their potential role in the brains of patients with Parkinson's and Alzheimer's diseases. Given that they are membranous vesicles, we speculate that EVs also have an intrinsic capacity to incorporate sphingolipids. In conditions under which 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.