# A non‐redundant role of EAAT3 for ATP synthesis mediated by GDH in dopaminergic neuronal cells: a new avenue for glutamate metabolism and protection in Parkinson's disease

## TL;DR

This study shows that activating GDH with BCH protects brain cells in Parkinson's disease and reveals a new role for EAAT3 in this process.

## Contribution

The study reveals a novel, non-redundant role of EAAT3 in GDH-dependent neuroprotection against Parkinson's disease.

## Key findings

- GDH activation with BCH improves cell viability and mitochondrial ATP synthesis in Parkinson's disease models.
- EAAT3 is functionally linked to GDH activity in protecting against PD injury.
- GDH activation reduces cellular redox burden in dopaminergic neurons.

## Abstract

Parkinson's disease (PD) is a devastating neurodegenerative disorder with a distinct loss of the nigrostriatal dopaminergic pathway. Despite the multiplicity in etiology, alterations that disrupt neuronal integrity can be traced back to defects in fundamental processes that typically run under mitochondrial inputs. Evidence indicates that mitochondrial activities are hierarchically integrated with the energetic performance of these organelles, so that an interesting perspective holds that interventions aimed at improving mitochondrial bioenergetics can potentially mitigate the severity of PD phenotype expression. In this mechanistic framework, approaches that facilitate the mitochondrial anaplerotic use of glutamate (Glut) might counteract the detrimental shift from Glut metabolism, which is typically altered in PD, to excessive Glut transmission that feeds excitotoxicity and the neurodegenerative spiral. In this study, we investigated whether the enhancement of glutamate dehydrogenase (GDH) activity, by using the GDH activator 2‐aminobicyclo‐(2,2,1)‐heptane‐2‐carboxylic acid (BCH), has neuroprotective potential against PD injury. In both retinoic acid‐differentiated SH‐SY5Y cells and primary rat mesencephalic neurons challenged with α‐synuclein plus rotenone to mimic PD, BCH‐dependent GDH activation significantly ameliorated cell viability, improved mitochondrial ATP synthesis and lessened to control levels the cellular redox burden. Strikingly, we collected evidence for the existence of a functional axis connecting GDH activity to a specific intracellular pool of the Excitatory Amino Acid Transporters (EAATs), namely the EAAT3. Overall, our results reveal a novel and non‐redundant role of EAAT3 for GDH‐dependent protection against PD injury, which may inspire new pharmacological approaches against PD pathology.

Parkinson's disease (PD) is a severe brain disorder caused by the loss of dopaminergic neurons. This study found that activating the enzyme glutamate dehydrogenase (GDH), by using the GDH activator BCH, protects cells and improves their energy production. It also highlights the previously undescribed role of EAAT3 in GDH‐dependent protection against PD injury, suggesting new potential treatments for the disease.