Acid Ceramidase Plays a Key Role in the Pathogenic Cascade Leading to Neurodegeneration in Gaucher and GBA1-associated Parkinson’s Disease
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Abstract
Brains from patients with neuronopathic GD (nGD) have high levels of glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph). GlcSph is generated through an alternative metabolic pathway in which GlcCer is deacylated by the lysosomal enzyme acid ceramidase. Using neurons from induced pluripotent stem cells (iPSCs) derived from patients with nGD, we found that mutant GBA1 caused autophagy/lysosomal pathway (ALP) dysfunction through hyperactivation of mTOR kinase, a key regulator of lysosomal function and metabolism. Treatment of nGD neurons with inhibitors of mTOR, or with GlcCer synthase inhibitors, prevented mTOR hyperactivation and restored lysosomal functions, suggesting that aberrant mTOR activation by glycosphingolipids is involved in pathogenesis. Further analysis showed that acid ceramidase inhibitors also reversed mTOR hyperactivity and rescued ALP function. Thus, preventing GlcSph formation was sufficient to rescue the severe phenotype of nGD neurons, pointing to elevated GlcSph as the lipid species responsible for lysosomal dysfunction in these neurons.