MidStriPD – Midbrain-Striatum-Assembloids to model synapse function alteration in Parkinson`s disease

About

Parkinson’s disease is a progressive neurological disorder. It is the second most common neurodegenerative disease after Alzheimer’s disease. Currently about seven million people are affected. A major disadvantage in 2D cell cultures of dopaminergic neurons as well as in midbrain organoids is the fact that in these models the dopaminergic neurons mainly form synapses with other dopaminergic neurons, while in vivo they form synapses with GABAergic spiny projection neurons in the striatum. Since one of the key proteins in the PD pathogenesis, alpha-Synuclein, is a synaptic protein, we hypothesise that the inadequate modelling of synaptic connections in current in vitro models reduces them predictively for disease-associated processes. Hence, we here follow the objective to develop a novel in vitro model, consisting of connected midbrain and striatum organoids (assembloid), recapitulating synaptic connections of midbrain dopaminergic neurons that are similar to those developed in vivo. We expect that, when we derive these assembloids from PD patient specific stem cells, alterations in these synaptic connections can be detected. Furthermore, we speculate that these synaptic alterations precede disease-associated processes like the loss of dopaminergic neurons. We assume that higher levels in alpha-Synuclein leads to alterations in synaptic number and/or function. These might be either increased or decreased.

In any case, if we detect synaptic alterations, rescuing them might have the potential to also rescue dopaminergic neuron loss. Since synapse function and stabilisation largely depends on the activity of growth factors like BDNF, GDNF, IGF and NGF, we suggest that modulating growth factor levels might also rescue other alterations, e.g. in synapse function and dopaminergic neuron number.