Secondary accumulation of lyso-platelet activating factors in lysosomal storage diseases

Lysosomal storage diseases (LSDs) are a group of inherited disorders caused by defects in genes that encode lysosomal enzymes, transmembrane proteins, or transport proteins. These defects typically lead to the accumulation of undegraded substrates or obstructed substances in lysosomes, serving as primary storage materials. However, in certain LSDs, secondary storage products—such as glycosphingolipids, phospholipids, and cholesterol—can also accumulate in tissues, independent of the primary enzyme or protein defect. In our recent studies, we identified lyso-platelet activating factors (lyso-PAFs) as secondary storage compounds in multiple LSDs, including Niemann-Pick disease type C1 (NPC1), GM2 activator deficiency, and GM1 gangliosidosis (GM1). Our ongoing work suggests that lyso-PAFs are also prevalent secondary storage products in Niemann-Pick disease type A (NPA), Sandhoff disease (SD), Tay-Sachs disease (TSD), and Krabbe disease (KD). We observed that elevated lyso-PAF levels were significantly correlated with the accumulation of primary storage substances in these disorders, indicating their potential as biomarkers for disease progression in these LSDs. Moreover, treatment with adeno-associated virus (AAV)-based gene therapies led to a reduction in lyso-PAF levels in the central nervous systems of TSD sheep and GM1 cats, further supporting their potential as biomarkers for therapeutic efficacy. While it remains unclear whether changes in lyso-PAFs contribute directly to disease pathology or simply reflect disease progression, further research into the enzymes involved in their synthesis and degradation is essential for uncovering their functional role in the cellular physiology and pathology of LSDs. Thus, further exploration of lyso-PAF in biofluids as prognostic and pharmacodynamic biomarkers is warranted.