The Fabry disease-associated lipid Lyso-Gb3 enhances voltage-gated calcium currents in sensory neurons and causes pain

Abstract

HighlightsGb3 and Lyso-Gb3, plasma lipids accumulating in Fabry disease, cause mechanical allodynia in mice.Lyso-Gb3 elevates intracellular calcium level in sensory neurons.Lyso-Gb3 enhances voltage-dependent calcium currents in small-diameter DRG neurons.Direct effects of lyso-Gb3 on sensory neurons may contribute to the pain of Fabry disease.

Lyso-glycosphingolipid abnormalities in different murine models of lysosomal storage disorders

“…Although patients with higher lysoGb3 levels showed a trend to more pronounced disease manifestations, no significant correlation of plasma lysoGb3 and specific symptoms was noted except for pain [35,36]. Very recently Choi and colleagues presented experimental evidence for a direct effect of lysoGb3 on sensory neurons [37]. It was reported that plantar administration of lysoGb3 induces mechanical allodynia in mice.…”

Nicotiana benthamiana α-galactosidase A1.1 can functionally complement human α-galactosidase A deficiency associated with Fabry disease

“…High costs of present α-galactosidase A preparations hamper the use of significantly higher doses. Secondly, the elevated circulating lysoGb3, considered to be toxic for podocytes and nociceptive neurons, is not completely corrected by present ERT 30,31 . Finally, a complicating factor with present ERT of FD proves to be the antigenicity of recombinant human α-galactosidase A in the majority of male FD patients that lack any endogenous enzyme (25).…”

“…In plasma of male FD patients and mice, lysoGb3 is several hundred-fold elevated, an abnormality that can be exploited for diagnosis and monitoring of disease progression and therapeutic correction (27)(28)(29)(30). Excessive lysoGb3 is toxic for nociceptive neurons and podocytes, which might explain the development of neuronopathic pain and renal failure in FD patients (31,32). Again, the formation of neutralizing antibodies in male FD patients receiving ERT is reported to impair reduction in plasma lysoGb3 (24).…”

Accurate quantification of sphingosine-1-phosphate in normal and Fabry disease plasma, cells and tissues by LC-MS/MS with 13 C-encoded natural S1P as internal standard

“…Symptomatic Fabry disease males show more than hundred fold elevated plasma globotriaosylsphingosine (lysoGb3) [45]. Correlations of elevated lysoGb3 with pain have been earlier observed [46] and more recently experimental evidence has been presented directly implicating lysoGb3 in the damage of nociceptive neurons [47]. Of note, S1P acting peripherally at S1P1 and S1P3 receptors can enhance sensitivity to various pain stimuli or elicit spontaneous pain [48], S1P can also act as antagonists of CB1 cannabinoid receptors involved in pain suppression [48].…”