Our group has a strong expertise on the generation of iPSC from adult human skin cells and on neural commitment and differentiation. In the last 10 years we have established cell reprogramming and genome editing technologies for disease in vitro modelling and drug screening. We have a large collection of iPSC derived from idiopathic or familial PD patients and healthy individuals as well as isogenic gene-corrected control and reporter human iPSC lines. Using iPSC-based technology we have modelled both idiopathic and familial PD and identified specific PD-related neurodegenerative phenotypes arising in differentiated dopamine neurons (Sánchez-Danés A., EMBO Mol Med, 2012; Orenstein S.J., Nat.Neur, 2013; Fernandez-Santiago R. et al., 2015; Calatayud C., et al., 2019).
By combining functional calcium imaging, biophysical modelling and lineage tracing of DAn, we have recently identified early alterations in PD neuronal function that were not present in control networks, and that predated the onset of neuron degeneration (Carola G. et al, Npj Parkinson’s disease, 2021). Additionally, we have developed a co-culture system of hiPSC-derived astrocytes and neurons to evaluate the contribution of glia to neuronal degeneration (di Domenico A. et al. 2019). Our studies identified LRRK2G2019S astrocytes as source of α-Syn spreading to neurons (di Domenico et al., 2019) and revealed a non-cell autonomous contribution of glial cells to PD-related neurodegeneration (di Domenico et al., 2019).
Our future projects and goals are:
- Define the role of glia and brain immune cells (microglia) in PD onset and progression
- Adopting gene editing approaches in our iPSC models to determine how specific targets influence protein aggregation and neuronal pathophysiology and to reveal mechanisms by which new protective genetic variants impact disease onset and progression.
- Developing midbrain organoids (hMO) to reproduce early stages onset of the disease and investigate PD-relevant pathomechanisms.
- Uncover early diagnostic markers and identify new molecular therapeutic targets for the development for new therapeutic strategy.