Hereditary sensory neuropathy type 1-associated deoxysphingolipids cause neurotoxicity, acute calcium handling abnormalities and mitochondrial dysfunction in vitro

The toxic sphingoid bases DSp and DMSp (or downstream metabolites) are released into the extracellular space where they destabilize neuronal cell membranes, resulting in dysfunction of neuronal ion channels such as store-operated Ca2+ (SOC) channels, upon stimulation. This results in elevated Ca2+ entry when SOC channels open, which is buffered by mitochondria. This increase in mitochondrial Ca2+ uptake in turn results in mitochondrial dysfunction, leading to loss of mitochondrial membrane potential and ultimately dysfunction of cellular processes and neuronal degeneration. (DSp: deoxysphinganine; DMSp: deoxymethylsphinganine).196