Fellows Lecture in Pairs: ‘Identifying druggable targets and exploring their therapeutic potential in complex iPSC-derived models of Parkinson’s’ and ‘Cooperation in the cortex-basal ganglia circuit’

Dr Charmaine Lang: ‘Identifying druggable targets and exploring their therapeutic potential in complex iPSC-derived models of Parkinson’s’

The discovery of induced pluripotent stem cells (iPSCs) has revolutionised the neurodegeneration field. iPSCs provide the ability to take, typically, skin cells from people with Parkinson’s, convert them into iPSCs (which have the unique property to turn into any cell type) and differentiate them into dopamine neurons. Although being the best human model available, one limitation of current iPSC approaches is that dopamine neurons do not act alone in the human brain but interact with many other cell types. Therefore, the formation of more sophisticated iPSC models, where multiple brain cell types interact is necessary for the drug discovery process. More sophisticated models will, ultimately, identify quality therapeutic candidates to put forward for clinical trials in the early treatment of Parkinson’s. My overall goals are the development of complex iPSC models which will study:

1. The interaction of dopamine neurons with astrocytes (an integral support cell in the brain) to identify whether a lack of support from neighbouring astrocytes is contributing to dopamine neuron loss in Parkinson’s
2. Screen repurposed compounds to identify those that reverse defects identified in Parkinson’s patient dopamine neurons
3. Use advanced devices which can grow iPSC dopamine neurons and astrocytes in specialised chambers to study whether physical interaction between dopamine neurons and astrocytes is necessary for drugs to rescue defects in dopamine neurons

I currently have two druggable therapeutic target projects underway including the transcriptional regulator of synaptic function, HDAC4 and the master transcriptional regulator of oxidative stress, NRF2. Not only will this work identify potential new therapeutic targets and drugs to treat Parkinson’s, but it will also lead on the development of new, more relevant “in a dish” models of mixed neuron/astrocyte co-cultures for drug screening purposes that could enter widespread use.

Dr Andy Peters: ‘Cooperation in the cortex-basal ganglia circuit’

The cortex and basal ganglia form an interconnected circuit involved in many aspects of learning and executing behavior. While these structures are typically studied separately, a key component in understanding their function is characterizing how activity flows between them. We approached this by combining widefield calcium imaging of the cortex with simultaneous Neuropixels electrophysiology in the striatum in behaving mice. This revealed a simple, topographic relationship between activity in the cortex and striatum. Further widefield recordings across learning described specific changes in cortical activity, which we will track through the basal ganglia and back to cortex in future work.