MITLIP_GBA

Homeostasis of some lipid classes, like ceramides, sphingolipids and cardiolipin, is frequently affected upon neurodegeneration, including Parkinson’s disease (PD). Experimental manipulation of these lipids can influence the penetrance of PD-causing mutations in disease models. This is particularly relevant in GBA1-linked PD, where mutations in the glucocerebrosidase 1 (GBA1) gene - encoding the lysosomal enzyme glucocerebrosidase (GCase) - disrupt lipid homeostasis, leading to the accumulation of toxic lipid species and contributing to disease penetrance and progression. This study aims to elucidate how GBA1 mutations disrupt cellular lipid homeostasis, with a particular emphasis on extra-lysosomal lipid metabolism, including mitochondrial lipid alterations affecting cellular energy metabolism. By integrating 3D neuronal disease models with advanced lipidomics and proteomics, we seek to uncover novel mechanisms by which lipid dyshomeostasis contribute to GBA1-PD pathology. Our findings will inform the development and evaluation of interventional strategies, including mitochondria-targeted approaches to restore cardiolipin homeostasis, designed to rebalance mitochondrial and cellular lipid metabolism and mitigate disease penetrance and progression.