Mucolipidosis type IV links TRPML-1 to renal tubulopatia

ABSTRACT: Loss of function mutations in the lysosomal channel TRPML-1 cause Mucolipidosis type IV, a rare lysosomal storage disease (LSD) characterized by neurological defects, progressive vision loss and achlorhydria.1–4 Recent reports described kidney disease and renal failure in MLIV patients in the second to the third decade of life5, although the molecular mechanisms underlying kidney disease and the physiological role of TRPML-1 in this organ remain unclear. By investigating kidney disease in the mouse model of TRPML-1 KO at different ages, we found an expansion of the lysosomal compartment and the accumulation of autophagic cargo during kidney disease progression. Also, Proximal Tubular Cells (PTCs) from TRPML-1 KO kidneys showed endocytosis defects. In vivo tracing using fluorescent β-Lactoglobulin confirmed a dramatic reduction in apical endocytosis. Excretome analysis of urine revealed that the lack of TRPML-1 results in proteinuria and enzymuria. Interestingly, TRPML-1 KO kidneys present inflammation, preceding lysosomal defects, with a dramatic upregulation of the macrophage markers F4/80 and Galectin-3. Older TRPML-1 KO mice also shown signs of fibrosis. Importantly, we observed a rescue of lysosomal and inflammatory phenotypes in TRPML-1 KO kidneys following AAV-mediated gene transfer of TRPML-1, providing direct evidence of the role of TRPML-1 in kidney function. Altogether, we demonstrate that TRPML-1 is a central player in apical endocytosis and absorptive function in PTCs, explaining kidney disease and opening novel therapeutic opportunities to prevent and treat these alterations in MLIV patients.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Urine

SUBMITTER: Diego L. Medina  

LAB HEAD: Diego Medina

PROVIDER: PXD049984 | Pride | 2026-04-06

REPOSITORIES: Pride