Pharmacological antagonism of kainate receptor rescues dysfunction and loss of dopamine neurons in a mouse model of human parkin-induced toxicity.

Maria Regoni,Michele Morari,Stefano Cattaneo,Letizia Zanetti,Flavia Valtorta,Daniela Mercatelli,Alessio Di Fonzo,Federica Albanese,Stefano Taverna,Giulia Maia Serratto,Salvatore Novello,Alice Passoni,Renzo Bagnati,Laura Croci,Maria Passafaro,Jenny Sassone,Gian Giacomo Consalez,Andrea Ciammola,Enrico Davoli

doi:10.1038/s41419-020-03172-8

Abstract

Mutations in the PARK2 gene encoding the protein parkin cause autosomal recessive juvenile Parkinsonism (ARJP), a neurodegenerative disease characterized by dysfunction and death of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). Since a neuroprotective therapy for ARJP does not exist, research efforts aimed at discovering targets for neuroprotection are critically needed. A previous study demonstrated that loss of parkin function or expression of parkin mutants associated with ARJP causes an accumulation of glutamate kainate receptors (KARs) in human brain tissues and an increase of KAR-mediated currents in neurons in vitro. Based on the hypothesis that such KAR hyperactivation may contribute to the death of nigral DA neurons, we investigated the effect of KAR antagonism on the DA neuron dysfunction and death that occur in the parkinQ311X mouse, a model of human parkin-induced toxicity. We found that early accumulation of KARs occurs in the DA neurons of the parkinQ311X mouse, and that chronic administration of the KAR antagonist UBP310 prevents DA neuron loss. This neuroprotective effect is associated with the rescue of the abnormal firing rate of nigral DA neurons and downregulation of GluK2, the key KAR subunit. This study provides novel evidence of a causal role of glutamate KARs in the DA neuron dysfunction and loss occurring in a mouse model of human parkin-induced toxicity. Our results support KAR as a potential target in the development of neuroprotective therapy for ARJP.

Highlights

Introduction Mutations in thePARK2 gene (OMIM 600116) cause the most common form of autosomal recessive juvenile Parkinsonism (ARJP), a neurodegenerative disease characterized by the loss of dopamine (DA) neurons in the substantia nigraOfficial journal of the Cell Death Differentiation AssociationRegoni et al Cell Death and Disease (2020)11:963Accruing evidence suggests that parkin plays an important role in the modulation of neurotransmission[5]
(see figure on previous page) Fig. 1 substantia nigra pars compacta (SNc) DA neurons of parkinQ311X mice display early kainate receptors (KARs) accumulation and degeneration. a Representative Western blot showing the levels of GluK2 subunit of KAR and GluA1 subunit of AMPAR in lysates prepared from the substantia nigra of WT or parkinQ311X mice at 1 month of age
This study provides novel evidence of the role of KARs in the DA neuron dysfunction and loss occurring in the parkinQ311X mouse, a model of human parkin-induced toxicity

Summary

Introduction

Accruing evidence suggests that parkin plays an important role in the modulation of neurotransmission[5]. Parkin localizes at both the presynaptic terminals, where it interacts with synaptic vesicles[6], and at the postsynaptic elements[7], where it interacts with the synaptic scaffolding molecules PSD-95, CASK7, and PICK18. Loss of parkin function was found to lead to GluK2 accumulation and increased KAR currents in glutamatergic neurons in vitro[9]. GluK2/KAR levels were increased in the brain tissues of parkin-knockout mice[10] and ARJP patients bearing PARK2 mutations[9]. KAR accumulation in DA neurons of ARJP models and patients might contribute to DA neuron dysfunction and, death

Methods

Results

Conclusion