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Distinct modes of balancing glomerular cell proteostasis in mucolipidosis type II and III prevent proteinuria

In a cell organelle called the lysosome cellular material is degraded via lysosomal enzymes. The lysosomal storage disorders mucolipidosis (ML) type II and III are caused by the missorting of lysosomal enzymes to the extracellular space instead of to the lysosomes. MLII and MLIII exhibit different disease severity. Patients with MLII exhibit severe lysosomal dysfunction resulting in multisystemic symptoms and early death, while MLIII patients exhibit moderate lysosomal dysfunction resulting in an attenuated clinical progression. In a few ML cases renal involvement has been described leading to the question whether this was coincidental or the result of lysosomal dysfunction.

To investigate the effect of lysosomal dysfunction on glomerular cells a MLII mouse model was generated and validated as well as compared to an established MLIII model. Both, MLII and MLIII mice, showed enlarged lysosomes in renal cells while renal morphology and function remained normal. The dysfunctional lysosomal degradation was distinctly compensated in MLII and MLIII mice. The lysosomal dysfunction in MLIII mice was compensated by enhancing the proteasomal protein degradation system, whereas MLII mice compensated the dysfunctional lysosomal protein degradation by the downregulation of protein synthesis.