Mechanism of TFEB Dysfunction by GBA1 Mutation in Human iPSC-derived Dopaminergic Neurons

Study Rationale:
People who have mutations in the GBA1 gene have a higher chance of developing Parkinson's disease (PD) but it is unclear why. We found that GBA1 mutations affect the cellular ability to clear proteins by disrupting regulation of the lysosomes. The lysosomes are responsible for recycling cellular components and inability to do this function can lead to neuronal death. Both levels and stability of the transcription factor EB (TFEB), the master regulator of the lysosome, were decreased in human GBA1 mutant neurons. We propose to identify how GBA1 mutation affects TFEB in order to develop therapies to restore its functions. 

Hypothesis:
GBA1 mutations lead to TFEB dysfunction in human iPSC derived-dopaminergic neurons

Study Design:
We will use stem cells, derived from human fibroblasts (induced-pluripotent stem cells or iPSCs), to generate dopaminergic neurons from control and GBA1 mutant cells. Using molecular and biochemical assays, we will determine if GBA1 mutations affect TFEB by disrupting its regulation and/or by altering the structure TFEB protein itself. We will also test if pharmacological or genetic correction of the enzyme deficiency caused by GBA1 mutation can reverse TFEB structural and functional alterations and restore lysosomal function in mutant neurons.

Impact on Diagnosis/Treatment of Parkinson's Disease (PD):
Our study will provide critical knowledge needed for developing therapies aiming at restoring TFEB ability to clear protein aggregates and reverse the neurodegenerative process in PD. It is also a key first step towards optimizing TFEB-based therapies and developing strategies to enhance its function in PD.

Next Steps for Development:
This study will help identify novel molecules involved in TFEB regulation, which is important for therapeutic development. Our human iPSC model can also be used to develop assays and screen for compounds capable of stabilizing TFEB and restoring its functions, which can aid significantly in the future development of TFEB-based therapies for PD.