Mapping human dopamine neuron diversity at single-cell resolution for enhanced stem cell therapy in Parkinson´s Disease

Midbrain dopamine (DA) neurons are a heterogeneous group of cells mainly comprising two major subgroups: A9 neurons control motor functions and are primarily degenerated in Parkinson´s disease (PD), whereas A10 neurons are largely unaffected by the condition and their dysfunction is associated with neuropsychiatric disorders.

Why A9 DA neurons are specifically severely affected in PD is currently unknown.This project aims to provide greater insights into the specific molecular mechanisms controlling the developmental program, maturation, and diversification of human A9 neurons.

An advanced single-cell transcriptomics approach in combination with innovative in vitro and in vivo human stem cell models will be used to: i) exploit the generation of distinct DA brain circuitries after human stem cell transplantation in animal models to obtain A9 / A10 transcriptional profiles based on target-specific outgrowth, ii) reconstruct and trace the developmental trajectory of A9 neurons in human brain assembloid, and iii) study the selective vulnerability of A9 neurons by modeling the disease in healthy and PD patient-derived human midbrain organoids to define underlying pathogenic factors and mechanisms.Determining PD patient-specific disease mechanisms will uniquely allow us to intervene in and reverse molecular dysfunction, leading to the generation of an autologous source of transplantable “treated” DA neurons, ultimately driving enhanced cell-based strategies for PD patients.