Fabry disease-associated globotriaosylceramide induces mechanical allodynia via activation of signaling through proNGF–p75NTR but not mature NGF–TrkA

Sugimoto, Junya; Satoyoshi, Hiroshi; Takahata, Kazue; Muraoka, Susumu

doi:10.1016/j.ejphar.2021.173882

Cited by 4 publications

(7 citation statements)

References 48 publications

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“…Unfortunately, often in FD patients ERT does not result in successful resolution of the SFN symptoms, neither alone or in association with typical pain treatments such as antiepileptics, antidepressant or opioids, that have also several side effects, including addiction [ [10] , [11] , [12] , [13] , [14] , [15] , [16] , [17] , [18] , [19] ]. The reason of incomplete response to ERT could be the presence of irreversible nerve damage.…”

Section: Discussionmentioning

confidence: 99%

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Relief of nocturnal neuropathic pain with the use of cannabis in a patient with Fabry disease

Bon,

Dardis,

Scarpa

et al. 2023

Molecular Genetics and Metabolism Reports

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Section: Discussionmentioning

confidence: 99%

“…The small fiber loss is higher in the distal long axons of the lower extremities [ 14 ]. Other mechanism such as inflammation and oxidative stress can contribute to Fabry neuropathy [ 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

Relief of nocturnal neuropathic pain with the use of cannabis in a patient with Fabry disease

Bon,

Dardis,

Scarpa

et al. 2023

Molecular Genetics and Metabolism Reports

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“…Inflammation has been postulated as a potential pathomechanisms of Fabry disease [ 48 ] with NGF being the key molecule mediating pain [ 49 , 50 , 51 , 52 ]. In experimental studies, treatment with a neutralising antibody against a precursor of NGF (proNGF) or its receptor, p75 NTR , led to the improvement in Gb3-induced allodynia [ 52 ]. It has been suggested that toxic concentration of Gb3 activates the pain pathway mediated through functional upregulation of proNGF–p75 NTR signalling [ 52 ].…”

Section: Pathophysiology Of Painmentioning

confidence: 99%

“…Inflammation has been postulated as a potential pathomechanisms of Fabry disease [48] with NGF being the key molecule mediating pain [49][50][51][52]. In experimental studies, treatment with a neutralising antibody against a precursor of NGF (proNGF) or its receptor, p75 NTR , led to the improvement in Gb3-induced allodynia [52].…”

Section: Inflammationmentioning

confidence: 99%

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Review of Mechanisms, Pharmacological Management, Psychosocial Implications, and Holistic Treatment of Pain in Fabry Disease

Rajan

Ireland

Johnson

et al. 2021

JCM

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Fabry disease is a progressive X-linked lysosomal storage disease caused by a mutation in the GLA gene, encoding the lysosomal hydrolase α-galactosidase A. The consequent reduced enzyme activity results in the toxic accumulation of glycosphingolipids, particularly globortriaosylceramide (Gb3 or GL3), in blood vessels, renal epithelia, myocardium, peripheral nervous system, cornea and skin. Neuropathic pain is the most common manifestation of Fabry disease and can be extremely debilitating. This often develops during childhood and presents with episodes of burning and sharp pain in the hands and feet, especially during exercise and it is worse with increased heat or fever. It is thought to be due to ischaemic injury and metabolic failure, leading to the disruption of neuronal membranes and small fibre neuropathy, caused by a reduced density of myelinated Aδ and unmyelinated C-fibres and alterations in the function of ion channels, mediated by Gb3 and lyso Gb3. It is important to confirm small fibre neuropathy before any Fabry disease treatment modality is considered. There is a clinical need for novel techniques for assessing small fibre function to improve detection of small fibre neuropathy and expand the role of available therapies. The current Fabry disease guidelines are in favour of pharmacological management as the first-line treatment for pain associated with Fabry disease. Refractory cases would benefit from a rehabilitation approach with interdisciplinary input, including medical, physiotherapy and psychological disciplines and including a Pain Management Programme.

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Age-related neuroimmune signatures in dorsal root ganglia of a Fabry disease mouse model

et al. 2023

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Pain in Fabry disease (FD) is generally accepted to result from neuronal damage in the peripheral nervous system as a consequence of excess lipid storage caused by alpha-galactosidase A (α-Gal A) deficiency. Signatures of pain arising from nerve injuries are generally associated with changes of number, location and phenotypes of immune cells within dorsal root ganglia (DRG). However, the neuroimmune processes in the DRG linked to accumulating glycosphingolipids in Fabry disease are insufficiently understood.Therefore, using indirect immune fluorescence microscopy, transmigration assays and FACS together with transcriptomic signatures associated with immune processes, we assessed age-dependent neuroimmune alterations in DRG obtained from mice with a global depletion of α-Gal A as a valid mouse model for FD. Macrophage numbers in the DRG of FD mice were unaltered, and BV-2 cells as a model for monocytic cells did not show augmented migratory reactions to glycosphingolipids exposure suggesting that these do not act as chemoattractants in FD. However, we found pronounced alterations of lysosomal signatures in sensory neurons and of macrophage morphology and phenotypes in FD DRG. Macrophages exhibited reduced morphological complexity indicated by a smaller number of ramifications and more rounded shape, which were age dependent and indicative of premature monocytic aging together with upregulated expression of markers CD68 and CD163.In our FD mouse model, the observed phenotypic changes in myeloid cell populations of the DRG suggest enhanced phagocytic and unaltered proliferative capacity of macrophages as compared to wildtype control mice. We suggest that macrophages may participate in FD pathogenesis and targeting macrophages at an early stage of FD may offer new treatment options other than enzyme replacement therapy.

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Fabry disease-associated globotriaosylceramide induces mechanical allodynia via activation of signaling through proNGF–p75NTR but not mature NGF–TrkA

Cited by 4 publications

References 48 publications

Relief of nocturnal neuropathic pain with the use of cannabis in a patient with Fabry disease

Relief of nocturnal neuropathic pain with the use of cannabis in a patient with Fabry disease

Review of Mechanisms, Pharmacological Management, Psychosocial Implications, and Holistic Treatment of Pain in Fabry Disease

Age-related neuroimmune signatures in dorsal root ganglia of a Fabry disease mouse model

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