Myelin lipid buildup links to lysosomal defects in mice

In mice, aging lysosomes in the cerebral cortex accumulate myelin lipids and proteins as sphingolipid breakdown shifts. Researchers used mass spectrometry to track longitudinal changes in the lipidome and proteome of cortical lysosomal fractions across mouse ages from 3 to 24 months. Applying multi-omics factor analysis, they identified an age-dependent increase in myelin components and evidence of altered sphingolipid catabolism that favors the degradation of sphingomyelins over glycosphingolipids. Experimental tests corroborated these predictions, showing that the age-dependent accumulation of myelin-derived glycosphingolipids was associated with lysosomal enlargement and dysfunction. This accumulation was most pronounced in microglia, producing organellar lipid changes that the authors note resemble lysosomal storage diseases.