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Significance Neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases, are major public health problems. Analysis of gene mutations that cause these diseases points to an important role of membrane trafficking within cells in disease development, but how such processes participate in the pathology is unclear. Here, we analyze a murine model of compromised membrane trafficking (due to mutation of a protein complex at the Golgi apparatus) and find metabolites of sphingolipids, molecules enriched particularly in the brain, accumulate in cells and tissues of this model. Preventing this buildup pharmacologically improved the symptoms of neurodegeneration and survival in these mice. Thus, our data provide evidence that modulating sphingolipid metabolism will provide a therapeutic avenue to treat some forms of neurodegenerative disease.

Inhibition of sphingolipid synthesis improves outcomes and survival in GARP mutant wobbler mice, a model of motor neuron degeneration