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

Abstract

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.

Co-Analysis of Serum and Urine Differentially Expressed Proteins in Mucopolysaccharidosis Type I

“…The downregulation of serum APOA1 and IGFBP3 affects lipid metabolism, cellular functions, growth processes, and lysosomal activity, potentially leading to intracellular waste accumulation, cellular toxicity, and tissue damage. In contrast, elevated levels of serum DPP4, ALDOB, SHBG, CRTAC1, LAMP2, SPP2, and CD163 are implicated in MPS I-related symptoms, encompassing impaired lysosomal transport, disrupted bile acid metabolism, alterations in the extracellular matrix, compromised lysosomal function, skeletal joint abnormalities − and immune dysregulation.…”

“…Secreted phosphoprotein 24 (SPP2) is a bone matrix protein that binds and inhibits bone morphogenic protein (BMP) . The biological activity of BMP and its endogenous antagonists is regulated by the extracellular matrix and cell surface HS proteoglycans.…”