NIH Research Festival
Free Sialic Acid Storage Disorder (FSASD) is a rare lysosomal storage disorder resulting from bi-allelic variants in SLC17A5. Patients with FSASD display significant hypomyelination, neurodegeneration, and altered lysosomal transport of sialic acid to the cytosol. To better understand the link between SCL17A5 function and neurodegeneration, we generated Slc17a5R39C knock-in mice with the prevalent p.Arg39Cys mutation. These mice exhibit features of FSASD, including progressive ataxia, neurodegeneration, and hypomyelination.
We examined the cortex, cerebellum, and cervical spinal cord of Slc17a5R39C mice and control littermates at developmental stages critical for neuronal development using immunofluorescence staining of Myelin basic protein (MBP), Purkinje cell protein 4 (PCP4) and glial fibrillary acidic protein (GFAP). Slc17a5R39C mice had decreased MBP expression, significant white matter astrogliosis, and decreased PCP4 expression over time, indicative of progressive Purkinje cell loss throughout development. Luxol Fast Blue staining, which highlights myelinated regions, revealed prominent hypomyelination in the corpus callosum, cerebellar white matter, and all major spinal white matter tracts as early as P14. Surprisingly, Nissl staining did not show differences in neuronal body numbers, suggesting myelin density changes are independent of neuronal loss.
Our findings suggest dysmyelination or hypomyelination has occurred prior to P14, during the biological window for myelination, resulting in myelination deficits in Slc17a5R39C mice. This is consistent with progressive neurodegeneration having occurred alongside myelination abnormalities. These results align with clinical presentation in FSASD patients and provide insights into the pathophysiology of FSASD and the role of SLC17A5 in myelin production, composition, and maintenance
Scientific Focus Area: Neuroscience
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