Impaired plasma membrane calcium ATPase activity and mitochondrial dysfunction contribute to calcium dysregulation in Fabry disease-related painful neuropathy

Abstract

Neuropathic pain is a hallmark symptom in Fabry disease (FD), a hereditary X-linked lysosomal storage disorder caused by a reduced activity of α-galactosidase A (α-Gal A). The α-Gal A deficiency results in the progressive accumulation of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) in the body fluids and lysosomes of various cell types, including sensory ganglia. The FD neuropathy affects the small thinly myelinated Aδ fibers and unmyelinated C fibers leading to the loss of intra-epidermal neuronal terminations, along with altered thermal and mechanical perception. Lipid accumulation, such as Gb3 and lyso-Gb3, is implicated in various cellular dysfunctions, including the alteration of ionic currents. It has been shown that administration of Gb3 to human umbilical vein endothelial cells leads to the downregulation of the calcium (Ca²⁺)-activated K⁺ channel K_Ca3.1, whereas lyso-Gb3 evokes cytosolic Ca²⁺ transients and an enhancement of voltage-activated Ca²⁺ currents in murine dorsal root ganglia. Therefore, we examined the mechanism underlying Ca²⁺ regulation in primary afferent neurons from the α-Gal A (−/0) mouse model. The obtained results suggest that other transport proteins participate in Ca²⁺ homeostasis in FD and their dysfunction may be directly involved in nociception. In this context, plasma-membrane Ca²⁺ ATPases exhibited reduced activity in FD, leading to an increased resting [Ca²⁺]_i in sensory neurons. The reduced activity was associated with a decrease of cytosolic pH which weakened the PMCA-dependent calcium extrusion. We finally evaluated the contribution of mitochondria to the Ca²⁺ signalling and we observed impairment of the mitochondrial buffer capacity, as well as dysfunctional mitochondria and enhanced autophagy/mitophagy. These findings provide a basis for future insights into the alterations of calcium signalling underlying the onset of neuropathic symptoms in FD.