Figure 1. Potential role of EVs in the spreading of toxic sphingolipids in sphingolipidoses.

A) In this model of general EVs mobilization, vesicles secreted by neurons and glial cells could potentially transfer pathological molecules into the cerebrospinal fluid (CSF) and across the blood-brain barrier (BBB), into the general circulation, with the possibility to transfer information to peripheral organs and tissues. Similarly, systemic EVs produced outside of the central nervous system might potentially transfer information to resident central cells. B) In this model of EVs-mediated transfer of toxic sphingolipids, lysosomal dysfunction elicits the accumulation of a particular sphingolipid “X” in those cells that actively synthetize that sphingolipid. This accumulation elicits cell-autonomous defects that interfere with cellular functions/structures (i.e. myelin, synapses, microglia). Affected cells may also secrete some of the accumulated sphingolipid “X” to the extracellular milieu via EVs. Secreted vesicles are internalized in non-affected cells via membrane fusion, endocytosis and lipid rafts-mediated endocytosis. Transfer of these “toxic” EVs may induce a “bystander effect”, inducing non-cell autonomous dysfunction. EVs: extracellular vesicles, LE: late endosomes, MVB: multivesicular bodies, PM: plasma membrane, PNS: peripheral nervous system and ECM: extracellular matrix.