TRPML-1 Dysfunction and Renal Tubulopathy in Mucolipidosis Type IV

Area of Science:

• Lysosomal biology
• Nephrology
• Genetic disease research

Background:

• Mucolipidosis type IV (MLIV) is a rare lysosomal storage disease caused by TRPML-1 mutations.
• MLIV is associated with neurological and visual impairment, and increasingly recognized kidney disease and failure.
• The molecular mechanisms underlying kidney dysfunction in MLIV are not well understood.

Purpose of the Study:

• To investigate the role of TRPML-1 in kidney function and disease pathogenesis in MLIV.
• To identify the cellular and molecular mechanisms of kidney impairment in MLIV.
• To explore potential therapeutic strategies targeting TRPML-1.

Main Methods:

• Cross-sectional review of medical records from 21 MLIV patients.
• Phenotypic analysis of MLIV mouse models and human kidney cells with TRPML-1 deficiency.
• Immunohistology, cell biology, urine proteomic analysis, and in vivo renal filtration measurements.
• Assessment of endolysosomal morphology, autophagy, endocytosis, inflammation, and fibrosis.

Main Results:

• Adult MLIV patients exhibited chronic kidney disease (stage 2-3) with decreased eGFR and proteinuria.
• MLIV mice showed impaired endolysosomal function, autophagy, and receptor-mediated endocytosis in kidney tubules.
• Accumulation of megalin (LRP2) and impaired uptake of ligands were observed in MLIV proximal tubular cells.
• Early-stage MLIV kidneys displayed inflammation, fibrosis, and NF-κB activation.
• AAV-mediated TRPML-1 gene delivery ameliorated kidney pathology in MLIV mice.

Conclusions:

• TRPML-1 dysfunction is directly linked to kidney disease development in MLIV.
• Impaired endolysosomal trafficking and autophagy are key mechanisms driving kidney pathology in MLIV.
• TRPML-1 is a critical determinant of kidney function and a potential therapeutic target for MLIV-associated kidney disease.