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

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.

• Authors: Maria Regoni, Stefano Cattaneo, Daniela Mercatelli, Salvatore Novello, Alice Passoni, Renzo Bagnati, Enrico Davoli, Laura Croci, Gian Giacomo Consalez, Federica Albanese, Letizia Zanetti, Maria Passafaro, Giulia Maia Serratto, Alessio Di Fonzo, Flavia Valtorta, Andrea Ciammola, Stefano Taverna, Michele Morari, Jenny Sassone
• Journal: Cell death & disease (Cell Death Dis) Vol. 11 Issue 11 Pg. 963 (11 10 2020) ISSN: 2041-4889 [Electronic] England
• PMID: 33173027 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Kainic Acid
• UBP 310
• Ubiquitin-Protein Ligases
• parkin protein
• Alanine
• Thymine

Topics

• Alanine (analogs & derivatives, pharmacology)
• Animals
• Disease Models, Animal
• Dopaminergic Neurons (drug effects, metabolism, pathology)
• Down-Regulation
• Female
• Male
• Mice
• Mice, Inbred C57BL
• Mutation
• Parkinson Disease (drug therapy, genetics, metabolism, pathology)
• Receptors, Kainic Acid (antagonists & inhibitors, metabolism)
• Thymine (analogs & derivatives, pharmacology)
• Ubiquitin-Protein Ligases (genetics, metabolism)
• GluK2 Kainate Receptor