Kainate receptor antagonists for pharmacological neuroprotection in Parkinson’s Disease

Background: Parkinson’s disease (PD) is a neurodegenerative disorder characterized by progressive dysfunction and death of dopamine (DA) neurons in the substantia nigra pars compacta (SNc) that project to striatum. Since synapse dysregulation and loss of synaptic homeostasis are recognized as early and key events in PD pathogenesis, it is conceivable that the early modulation of appropriate synaptic targets provides neuroprotection.

Rationale and objectives: We aim at investigating a novel synaptic target in PD pharmacotherapy, namely the kainate receptor (KAR). KAR is a druggable glutamate receptor subtype that until now has received much less attention than other receptors, despite its well-recognized ability to modulate neurotransmission, neuronal excitability and synaptic plasticity. Preclinical studies from our and other groups have shown that KAR is expressed in DA neurons and contributes to DA neuron death in a genetic form of juvenile PD. Studies also indicate that pharmacological KAR modulation might provide neuroprotection in PD.

Since a neuroprotective therapy for PD is still lacking, research efforts aimed at validating novel targets for neuroprotection are critically needed. In this project, we will test the hypothesis that pharmacological antagonism of KAR provides neuroprotection in preclinical models of genetic and idiopathic PD, and investigate the underlying cellular and molecular mechanisms of neuroprotection.

 Research team and available resources: The project involves three Units with proven and complementary expertise in the study of synaptic mechanisms in physio-pathological conditions and in the molecular/cellular neurobiology of PD. Preclinical models for this project are already available in the laboratories of the participants and include state-of-the-art in vivo murine models of genetic juvenile PD (parkinR275W knock-in mouse) and idiopathic PD (iPD) (based on overexpression or spreading of alpha Synuclein (aSyn)), along with in vitro human DA neurons (iDA) carrying PD-associated mutations derived from human induced pluripotent stem cells (iPSCs). The three Units have been collaborating for several years, as shown by several common publications and by the preliminary data deriving from their ongoing collaboration.