The origin and three-dimensional structure of urinary mulberry bodies in fabry disease

Fabry disease (FD) is a congenital metabolic disorder characterized by the accumulation of globotriaosylceramide (Gb3) due to deficient alpha-galactosidase A (GLA) activity. Although the presence of urinary mulberry bodies (uMBs) in FD is well documented, their precise origins and molecular composition remain poorly understood. In the present study, we performed comprehensive morphological, molecular, pathological, and structural analyses of uMBs. Our results revealed that uMBs are dynamic structures that exhibit substantial structural plasticity in response to fluid flow. We demonstrated that uMBs originate from podocytes rather than renal tubular cells and are primarily composed of lysosome-derived structures. Furthermore, we identified glomerular basement membrane components within these podocyte-derived uMBs, suggesting a complex shedding process in the urine. Three-dimensional reconstruction with confocal laser scanning microscopy was used to successfully visualize the complex internal architectures of these structures. Experiments using GLA knockout cells suggested a potential association between Gb3 accumulation and the induction of cell death via the JNK signaling pathway. These findings provide novel insights into the structural characteristics and pathological relevance of uMBs in the pathogenesis of FD nephropathy.