Publication — IRIC
Severe kidney dysfunction in sialidosis mice reveals an essential role for neuraminidase 1 in reabsorption.
Sialidosis is an ultrarare multisystemic lysosomal disease caused by mutations in the neuraminidase 1 (NEU1) gene. The severe Type II form of the disease, manifests with a prenatal/infantile or juvenile onset, bone abnormalities, severe neuropathology and visceromegaly. A subset of these patients presents with nephrosialidosis, characterized by abrupt onset of fulminant glomerular nephropathy. We studied the pathophysiological mechanism of the disease in two NEU1-deficient mouse models, a constitutive Neu1 knockout Neu1∆Ex3 and a conditional phagocyte-specific knockout Neu1Cx3cr1ΔEx3. Mice of both strains exhibited terminal urinary retention and severe kidney damage with elevated urinary albumin levels, loss of nephrons, renal fibrosis, presence of storage vacuoles and dysmorphic mitochondria in the intraglomerular and tubular cells. Glycoprotein sialylation in glomeruli, proximal and distal tubules was drastically increased including that of an endocytic reabsorption receptor megalin. The pool of megalin bearing O-linked glycans with terminal galactose residues, essential for protein targeting and activity, was reduced to below detection levels. Megalin levels were severely reduced, and the protein was directed to lysosomes instead of the apical membrane. Together, our results demonstrated that desialylation by NEU1 plays a crucial role in processing and cellular trafficking of megalin and that NEU1 deficiency in sialidosis impairs megalin-mediated protein reabsorption.