Abstract
Fabry disease (FD) is one of the X-linked lysosomal storage disorders caused by deficient functioning of the alpha-galactosidase A (α-GalA) enzyme. The α-GalA deficiency leads to multi-systemic clinical manifestations caused by the preferential accumulation of globotriaosylceramide in the endothelium and vascular smooth muscles. A hallmark symptom of FD patients is peripheral pain that appears in the early stage of the disease. Pain in FD patients is a peripheral small-fiber idiopathic neuropathy, with intra-epidermal fiber density and integrity being used for diagnosing FD in humans. However, the molecular correlates underlying pain sensation in FD remain elusive. Here, we have employed the α-GalA gene KO mouse as a model of FD in rodents to investigate molecular changes in their peripheral nervous system that may account for their algesic symptoms. The α-GalA null mice display neuropathic pain as evidenced by thermal hyperalgesia and mechanical allodynia, with histological analyses showing alterations in cutaneous innervation. Additionally, KO mice showed a decreased and scattered pattern of neuronal terminations consistent with the reduction in neuronal terminations in skin biopsies of patients with small fiber neuropathies. At the molecular level KO animals showed an increase in the expression of TRPV1 and Nav1.8, and a decrease in the expression of TRPM8. Notably, these alterations are observed in young animals. Taken together, our findings imply that the α-GalA KO mouse is a good model in which to study the peripheral small fiber neuropathy exhibited by FD patients, and provides molecular evidence for a hyperexcitability of small nociceptors in FD.
Highlights
Neuropathic pain is a very common and disabling symptom in numerous small fiber neuropathies (SFN), involving at the same time sensory and emotional experiences
From offspring mice were extracted and genotyped by PCR amplification, using three oligonucleotide primers: the WT locus amplified a band of 295 bp, the targeted locus amplified a band of 202 bp, whereas the heterozygous females were distinguished by the presence of both amplified bands (Figure 1A)
This increase was even more significant after 12 weeks (p12weeks = 0.0111, n = 10 animals for WT, n = 5 animals for knock out (KO)) suggesting that the accumulation of Gb3 in diverse organs of Fabry disease (FD) male (a-GalA(2/0)) body leads to an increment in weight
Summary
Neuropathic pain is a very common and disabling symptom in numerous small fiber neuropathies (SFN), involving at the same time sensory and emotional experiences. One of such SFNs, Fabry disease (FD) is a hereditary X-linked metabolic storage disorder due to insufficient amounts or a complete lack of the lysosomal enzyme a-galactosidase A (a-GalA). FD is a multi-system disorder, with an extremely wide range of physical signs and symptoms related to the gender of the affected patient. Heterozygous female patients with FD exhibit heterogeneous phenotypic variations of the clinical features, ranging from asymptomatic to severe symptoms due to random X-chromosomal inactivation [2,3,4]
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