A new study from OPDC Career Development Fellow Natalie Connor-Robson investigates how mutations in the gene LRRK2, which are known to cause Parkinson’s, effect normal cell function. We generated dopaminergic neurons, the cells that are affected in Parkinson’s, from stem cells reprogrammed using skin samples donated by people with Parkinson’s who carry LRRK2 mutations. These neurons were used for in depth analysis which showed the most altered pathway in these cells was endocytosis. Endocytosis is a pathway essential to neurons for their normal function, which helps the neurons to communicate with each other and is also important for recycling cellular waste.
We also saw similar changes in our aged LRRK2 rats which have the same LRRK2 mutations found in people with Parkinson’s.
Finally, we used human post-mortem brain tissue from people who had LRRK2 mutations to show that the endocytosis pathway was also disturbed in the people with Parkinson’s.
- iPSC-derived dopaminergic neurons from LRRK2 patients show extensive endocytic changes.
- Integrated proteomic and transcriptomic approach reveals dysregulation of 25 RABs.
- Functional impairment of clathrin mediated endocytosis in LRRK2 iPSC-dopaminergic neurons.
- Aged LRRK2 rats also show similar perturbations of key endocytic proteins.
- LRRK2 human post-mortem tissue shows upregulation of clathrin and endophilin.