Altered lipid homeostasis underlies selective neurodegeneration in SNX14 deficiency

Dysregulated lipid homeostasis is emerging as a potential cause of neurodegenerative disorders. However, evidence of errors in lipid homeostasis as a pathogenic mechanism of neurodegeneration remains limited. Here, we show that the cerebellar neurodegeneration caused by SNX14 deficiency is associated with lipid metabolism defects. Recent in vitro and in silico studies indicate that SNX14 is an inter-organelle lipid transfer protein that regulates lipid droplet biogenesis and fatty acid desaturation, suggesting that human SNX14 deficiency belongs to an expanding class of cerebellar neurodegenerative disorders caused by altered cellular lipid homeostasis. To test this hypothesis, we generated a mouse model that recapitulates the human SNX14 deficiency at genetic and phenotypic level. Through histological and transcriptomic analyses, we demonstrate that cerebellar Purkinje cells are selectively vulnerable to SNX14 deficiency, while forebrain regions preserve their neuronal content. Ultrastructure and lipidomic studies reveal widespread lipid storage and metabolism defects in SNX14 deficient mice. Furthermore, we identify a unique lipid metabolite profile that links the accumulation of acylcarnitines with the selective cerebellar neurodegeneration in SNX14 deficiency. These findings highlight the importance of lipid homeostasis for neuronal function and survival and suggest a mechanism for selective cerebellar vulnerability to altered lipid homeostasis.