Understanding the molecular pathogenesis of GBA1-associated Parkinson's disease by using engineered induced pluripotent stem cells

• Applicant: Michela Deleidi, Ph.D.
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: from 2014 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 264574831

Mutations in the acid beta-glucocerebrosidase (GBA1) gene, which encodes the lysosomal enzyme glucocerebrosidase (GCase), are the strongest genetic risk factor for Parkinson s disease (PD) known to date. Homozygous mutations of GBA1 are responsible for Gaucher's disease (GD), which is the most prevalent lysosomal storage disorder characterized by decreased activity of GCase and subsequent accumulation of glucosylceramide in several organs including the brain. In recent years, GD and PD have been connected on account of the clinical observation of parkinsonism and Lewy Body pathology in patients with GD. GCase plays a role in lipid metabolism and function of lysosomes, and this finding has led to a wide variety of models to explain how gene defects cause PD and other synucleinopathies. By using human neuronal models of neurodegeneration, we have found that GBA1 mutations cause lysosomal/autophagic dysfunction and impaired calcium dynamics. We now propose to expand upon our previous results to unravel the molecular mechanisms of GBA1-associated PD. To this end we will use engineered induced pluripotent stem cells (iPSCs) and differentiate them into dopaminergic neurons. Specifically, the aims of the current proposal are: 1) To investigate the role of loss vs gain of function in GBA1-associated neurodegeneration by generating GBA1 knockout iPSC lines; 2) To investigate whether GBA1 mutations trigger mitochondrial dysfunction; 3) To investigate whether GBA1 mutations trigger endoplasmic reticulum stress by gain of function mechanisms. We believe that understanding the role of genetic risk factors in PD pathogenesis will give important clues regarding the causes of familial and sporadic PD, and will lead to the discovery of novel therapeutic targets and disease biomarkers.

• DFG Programme: Research Grants