Parkinson’s disease (PD) is a progressive neurodegenerative disorder that lacks effective treatment strategies to halt or delay its progression. The homeostasis of Ca²⁺ ions is crucial for ensuring optimal cellular functions and survival, especially for neuronal cells. In the context of PD, the systems regulating cellular Ca²⁺ are compromised, leading to Ca²⁺-dependent synaptic dysfunction, impaired neuronal plasticity, and ultimately, neuronal loss. Recent research efforts directed toward understanding the pathology of PD have yielded significant insights, particularly highlighting the close relationship between Ca²⁺ dysregulation, neuroinflammation, and neurodegeneration. However, the precise mechanisms driving the selective loss of dopaminergic neurons in PD remain elusive. The disruption of Ca²⁺ homeostasis is a key factor, engaging various neurodegenerative and neuroinflammatory pathways and affecting intracellular organelles that store Ca²⁺. Specifically, impaired functioning of mitochondria, lysosomes, and the endoplasmic reticulum (ER) in Ca²⁺ metabolism is believed to contribute to the disease’s pathophysiology. The Na+-Ca²⁺ exchanger (NCX) is considered an important key regulator of Ca²⁺ homeostasis in various cell types, including neurons, astrocytes, and microglia. Alterations in NCX activity are associated with neurodegenerative processes in different models of PD. In this review, we will explore the role of Ca²⁺ dysregulation and neuroinflammation as primary drivers of PD-related neurodegeneration, with an emphasis on the pivotal role of NCX in the pathology of PD. Consequently, NCXs and their interplay with intracellular organelles may emerge as potentially pivotal players in the mechanisms underlying PD neurodegeneration, providing a promising avenue for therapeutic intervention aimed at halting neurodegeneration.

Increasing evidence suggests that metabolic alterations may be etiologically linked to neurodegenerative disorders such as Parkinson’s disease (PD) and in particular empathizes the possibility of targeting mitochondrial dysfunctions to improve PD progression. Under different pathological conditions (i.e., cardiac and neuronal ischemia/reperfusion injury), we showed that supplementation of energetic substrates like glutamate exerts a protective role by preserving mitochondrial functions and enhancing ATP synthesis through a mechanism involving the Na⁺-dependent excitatory amino acid transporters (EAATs) and the Na⁺/Ca²⁺ exchanger (NCX). In this study, we investigated whether a similar approach aimed at promoting glutamate metabolism would be also beneficial against cell damage in an in vitro PD-like model. In retinoic acid (RA)-differentiated SH-SY5Y cells challenged with α-synuclein (α-syn) plus rotenone (Rot), glutamate significantly improved cell viability by increasing ATP levels, reducing oxidative damage and cytosolic and mitochondrial Ca²⁺ overload. Glutamate benefits were strikingly lost when either EAAT3 or NCX1 expression was knocked down by RNA silencing. Overall, our results open the possibility of targeting EAAT3/NCX1 functions to limit PD pathology by simultaneously favoring glutamate uptake and metabolic use in dopaminergic neurons.