Transcription factors in Parkinson´s disease

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of midbrain dopaminergic neurons (mDAs). The treatment of PD is currently symptomatic and there is no cure.

Transplantation of human midbrain fetal tissue has provided proof of concept that cell replacement therapy can change the course of disease.The cause of PD is largely unknown. 10% of the cases have a genetic cause, but most of them are thought to arise from the interaction between genetic and environmental risk factors.

By integrating PD-GWAS and scRNA-seq data we recently found that transcription factors and regulators (TF/Rs) in mDAs are associated to PD (Bryois et al, 2020, Nat Genetics).

We previously found that PBX1, a TF required for the development and maintenance of mDAs, is nearly lost in PD (Villaescusa et al, 2016, EMBO).Here we propose to: 1) Identify changes in the expression and regulation of TF/Rs in PD brain tissue and induced pluripotent stem cells (iPSCs) using single cell technologies (LaManno et al, 2016, Cell). 2) Determine their function and contribution to PD by CRISPR activation and repression in iPSCs. 3) Use TF/Rs to generate disease-resistant mDAs for cell replacement in PD models, by transplantating human pluripotent stem cell-derived mDA progenitors, or by in vivo reprogramming of brain astrocytes (Rivetti et al, 2017, Nat Biotech).This project will increase our understanding of the role of TF/Rs in PD and will develop novel cell replacement strategies for PD.