Effects of Calcium Ion Dyshomeostasis and Calcium Ion-Induced Excitotoxicity in Parkinson’s Disease

Abstract

Calcium ions (Ca²⁺) are vital intracellular messengers that regulate a multitude of neuronal functions, including synaptic transmission, plasticity, exocytosis, and cell survival. Neuronal cell death can occur through a variety of mechanisms, including excitotoxicity, apoptosis, and autophagy. In the context of excitotoxicity, the excessive release of glutamate in the synapses can trigger the activation of postsynaptic receptors. Upon activation, Ca²⁺ influx into the cell from the extracellular space via their associated ion channels, most notably L-type Ca²⁺ channels. Previous studies have indicated that α-synuclein (α-syn), a typical cytosolic protein, plays a significant role in the pathogenesis of Parkinson’s disease (PD). It is also worth noting that the aggregated form of α-syn has the capacity to affect Ca²⁺ homeostasis by altering the function of Ca²⁺ regulation. The upregulation of leucine-rich repeat kinase 2 (LRRK2) is closely associated with PD pathogenesis. LRRK2 mutants exhibit a dysregulation of calcium signaling, resulting in dopaminergic neuronal degeneration. It could therefore be proposed that α-syn and LRRK2 play important roles in the mechanisms underlying Ca²⁺ dyshomeostasis and excitotoxicity in PD.

1. Introduction

Recently, calcium ions (Ca²⁺) have been implicated in neurodegenerative diseases. Ca²⁺ regulation is associated with various ion channels and transporters in the plasma and endoplasmic reticulum (ER) membranes [1]. Although ion channels and transporters regulate ion homeostasis, abnormal ion permeability of the channel and activation of the transporter can result in Ca²⁺ dyshomeostasis, leading to mitochondrial and ER dysfunction and Ca²⁺-dependent excitotoxicity [2]. These dysfunctions can increase cytosolic Ca²⁺ concentrations through Ca²⁺-dependent mechanisms. Excess Ca²⁺ further promotes excitotoxicity, which may be an important driver of neuronal cell death during aging [1].

Excitotoxicity has been shown to contribute to multiple acute central nervous system (CNS) disorders, including epilepsy, ischemia, stroke, traumatic brain injury, and spinal cord injury. Excitotoxicity has further been implicated in chronic age-related neurodegenerative diseases, such as Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). Glutamate is a major excitatory neurotransmitter in the CNS [3]. Excitotoxicity is caused by the excessive release of glutamate and the subsequent glutamate-mediated activation of postsynaptic receptors; however, Ca²⁺ dyshomeostasis is the key mediator of excitotoxic damage [4,5]. PD is a progressive neurodegenerative disease characterized by motor dysfunction including resting tremors, rigidity, and bradykinesia [6]. Loss of the substantia nigra pars compacta (SNc) is a major pathological cause of PD. Inclusion bodies, called Lewy bodies (LBs), are found in the SNc of patients with PD [7]. Many studies have investigated the mechanisms of cell death of dopaminergic neurons in the midbrain, with results showing that this process is an important driver of the motor abnormalities associated with PD [8]. Recently, the pathological progression of LB from the lower stem nuclei to the cortical region was hypothesized to be the second symptom of PD and dementia [9]. Although the cause of PD remains unclear, previous studies investigating idiopathic PD have shown an increase in α-synuclein (α-syn) aggregation [10]. α-Syn is associated with several critical mechanisms of dopaminergic cell death, including oxidative stress, mitochondrial dysfunction, ER stress, and apoptosis [11]. Studies have begun to elucidate the pathological function of α-syn, with some research showing that plasma membrane cation permeability may be disrupted by abnormal α-syn [12]. Leucine-rich repeat kinase 2 (LRRK2) also plays a role in the pathogenesis of PD, and its kinase activity is a key driver of dopaminergic neuronal degeneration [13]. The pathomechanism of LRRK2 is related to mitochondrial dysfunction, the autophagy–lysosome pathway, and cellular senescence in dopaminergic neuron [14,15]. Facets of Ca²⁺ dyshomeostasis and Ca²⁺-dependent excitotoxicity in PD progression affected by α-syn or LRRK2 are discussed in this study.

2. Regulation of Calcium Ion and Its Pathogenesis

2.1. Ca²⁺ Homeostasis

Ca²⁺ is a central intracellular messenger that regulates many cellular functions, including cell differentiation, growth, synaptic activity, exocytosis, and cell survival. The intracellular Ca²⁺ concentration ([Ca²⁺]i) is important in determining the physiological state of the cell. In the resting state, [Ca²⁺]i is maintained at low levels of 50–300nM [16]. Neurons regulate [Ca²⁺]i through Ca²⁺ buffering, Ca²⁺ influx/efflux, and intracellular Ca²⁺ storage. Under physiological conditions, these multiple processes ensure proper and independent Ca²⁺-regulated signaling cascades [17]. However, excessive Ca²⁺ influx or over-release of Ca²⁺ from cellular stores into the cytosol can trigger an excessive Ca²⁺ regulation mechanism [18]. This mechanism involves the conversion of a Ca²⁺-independent process into a Ca²⁺-dependent process that is usually dominant or operating at a low level [19]. Inappropriate activation of Ca²⁺-dependent processing is caused by oxidative stress, lipid peroxidation, or the membranous deposition of aggregated proteins, made of amyloid ß (Aß), α-syn, and huntingtin (Htt), which impair pumps and calcium channels in cells and ER membranes [4]. The increase in and spread of protein aggregates through the brain tissues are known to be associated with the progression of neurodegenerative diseases, and neurodegenerative diseases are also related to aging [20]. Moreover, as aggregated forms of proteins which induce oxidative stress, neuronal cells become sensitized to excitotoxicity. Therefore, age-related neurodegenerative diseases are associated with aggregate-induced excitotoxicity [21,22].

2.1.1. Increase in Ca²⁺ Influx via the Plasma Membrane

The influx of Ca²⁺ through voltage-dependent and ligand-gated channels in the plasma membrane stimulates neurotransmitter release from presynaptic neurons and the responses of postsynaptic neurons [23]. Glutamate increases Ca²⁺ influx by directly activating N-methyl-D-aspartate receptors (NMDARs) and 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propionate receptors (AMPARs) and by indirectly activating voltage-gated Ca²⁺ channels (VGCCs) (Figure 1) [24].

The activation of NMDARs can trigger a variety of cellular responses, including apoptosis through an extrasynaptic NMDAR-mediated signaling cascade, neuronal plasticity through the activation of postsynaptic NMDARs, and long-term potential (LTP) or long-term depression (LTD) through the regulation of Ca²⁺ levels [24]. Similarly to the AMPAR subunits, NMDARs have five subunits, termed NR1 and NR2A-D [25]. Each subunit comprises four extracellular amino-terminal domains, a membrane domain, and an intracellular C-terminal tail [26]. The NR1 subunit has eight functional splice variants (NR1 a-h) and one non-functional truncated splice variant, whereas the NR2 subunits have only NR2D splice variants. An asparagine residue (N598) in the NR1 subunit within the channel pore loop structure of the second membrane domain controls the Ca²⁺ permeability of the receptors [27]. Furthermore, in NR1 mutant mice (N598Q and N598R), NMDAR-mediated signaling disrupts autonomic function, including feeding and breathing failure [22]. These findings indicate that NMDARs are critical for Ca²⁺ permeability. The NR2 subunits exhibit a developmental switch in expression [28]. The expression of NR2B and NR2D begins at E14, whereas NR2A and NR2B are detected perinatally [29]. The NR2A subunit is associated with a Ca²⁺-dependent process under excitotoxic conditions. In one study, Bessho et al. indicated a possible correlation between increased NR2A levels and NMDAR-mediated Ca²⁺ influx by upregulating the NR2A subunit mRNA via Ca²⁺ influx through VGCCs [30,31]. Following the K⁺-induced depolarization of cerebellar granule cells, these cells, which upregulate the NR2A subunit mRNA via Ca²⁺ influx through VGCCs, become more susceptible to NMDA-mediated toxicity. Mouse model studies have further shown that NR2A deficiency results in a significant reduction in infarct volume [22].

Although AMPARs have a high affinity for glutamate, they are Ca²⁺-impermeable [32]. As such, AMPARs are thought to induce membrane depolarization by facilitating Na⁺ influx. AMPAR-mediated depolarization opens both VGCC and removes the Mg²⁺ block from NMDARs, allowing for Ca²⁺ influx through these pathways [27]. Recently, the GluR2 subunit of AMPAR has been proposed to control the Ca²⁺ permeability of these channels. GluR2 null mice exhibit high Ca²⁺ permeability and expression levels [22]. Chronic treatment of 6-OHDA-lesioned rats with L-dopa has further been shown to trigger dyskinesia [33]. A further study investigated the effected treatment with antagonists of NMDARs and AMPDRs administered alone or in combination after 21 days of L-dopa treatment [34]. The results showed that single-drug administration exerted no antagonist effect, while co-administration achieved a better improvement in behavior than the placebo or single treatment. A primate study also showed that co-administration of NMDARs and AMPARs antagonists alleviates dyskinesia [35], supporting the hypothesis that NMDARs and AMPARs antagonists can block Ca²⁺ influx and attenuate the effects of excitotoxicity [36]. VGCCs are found only in excitable cells and exist in several different types: N- and P/Q-type in axonal buttons, which regulate Ca²⁺-dependent neurotransmitter release; and L-type in dendrites, which mediate Ca²⁺-dependent gene expression. VGCCs are activated by membrane depolarization or the opening of NMDARs and AMPARs. Interestingly, L-type VGCCs are important for PD progression, SNc loss, and dopaminergic neuron death [37]. Unlike most neurons in the brain, SNc dopaminergic neurons are autonomously active [38]. Accordingly, SNc dopamine neurons continuously generate action potentials in the absence of synaptic input, in a process known as pacemaking. The L-type channels underlying pacemaking in SNc dopaminergic neurons have a pore-forming Cav1.3 subunit rather than a cardiac Cav1.2 subunit [37]. The Cav1.3 channel is more age-dependent and opens at more hyperpolarized membrane potentials than the Cav1.2 channel [37,38]. Although the Cav1.3 channels control pacemaking in dopaminergic neurons, blocking Cav1.3 can protect against MPTP- and rotenone-induced loss of dopaminergic neurons in the SNc [39,40]. It has further been reported that Cav2.3 and NCS-1 are involved in the progression of PD and can be regarded as therapeutic targets for Ca²⁺-dependent neurodegeneration in PD [41]. Slow Ca²⁺ clearance is mediated by Ca²⁺ pumps and exchangers [42]. Plasma membrane Ca²⁺-ATPase (PMCA) pumps Ca²⁺ against a concentration gradient of four orders of magnitude. The Na⁺/ Ca²⁺ exchanger in the plasma membrane (Figure 1) removes Ca²⁺ from the cytosol.

Previous studies have shown that the activation of glutamate receptors causes changes in the levels of intracellular cations, particularly an increase in Ca²⁺ concentration [43]. As such, the [Ca²⁺]i of neurons increases beyond a tolerable level, resulting in the overactivation of glutamate receptors and the acceleration of cell death, in a process termed excitotoxicity [4,5]. Under adverse conditions, glutamate receptor activation can trigger neuronal cell death [44]. For example, oxidative stress, including cell death associated with peroxide anion radicals, hydrogen peroxide, hydroxyl radicals, and peroxynitrite, renders neurons susceptible to excitotoxicity by impairing Ca²⁺ regulation [45]. Lipid peroxidation caused by hydroxyl radicals and peroxynitrite can further induce membrane-associated oxidative stress (MAOS), which damages the cell membrane and lipoproteins by oxidizing membrane lipids [46]. MAOS disrupts the function of ionotropic ATPases, including Na⁺/K⁺-ATPases, Ca²⁺-ATPases, and glutamate and glucose transporters [47,48,49,50]. MAOS is also responsible for an increase in Ca²⁺ influx via NMDARs and VGCCs [51,52]. Neurotoxic or pathogenic agents and disease-associated mutations are also associated with excitotoxicity [22].

Therefore, excitotoxicity due to the abnormal regulation of calcium ions through the protein machineries of the cell membrane is expected to be related to PD progression, and, at the same time, PD-related drugs and genetic factors may interfere with the mechanism that regulates calcium ion concentration.

2.1.2. Mobilization of Ca²⁺ Signals in Cells

The Ca²⁺-binding protein (Figure 2i) contains a helix–loop–helix motif (EF-hand) that functions as a Ca²⁺ sensor and transmitter [53]. Ca²⁺ is coordinated by several acidic residues in this loop. Differences in Ca²⁺ protein localization, Ca²⁺ affinity, and Ca²⁺ binding kinetics are all important in distinguishing between different Ca²⁺ signals. The Ca²⁺-binding proteins in neurons include the ubiquitous calmodulins, S100 proteins, calmyrins, and neuronal Ca²⁺ sensors (NCSs). There are several mechanisms through which Ca²⁺ signals can be transmitted to cellular effectors. In general, the EF-hand protein binds to its target protein following a conformational change caused by Ca²⁺ binding [54]. Ca²⁺-mediated changes in the intracellular localization of Ca²⁺-binding proteins result in the transduction of Ca²⁺ signals. The downstream molecular events of Ca²⁺ signaling are complex and involve phosphorylation cascades. Ca²⁺ signaling is mediated by Ca²⁺ and calmodulin-dependent protein kinase or CaM kinase (CaMKI-IV), protein kinase C, protein kinase A, IP3 kinase, Ca²⁺-dependent phosphatase calcineurin B, cAMP phosphodiesterase, adenylyl cyclase, Ca²⁺-dependent neuronal nitric oxide synthase (NOS), and calpains. Some Ca²⁺ signaling cascades can reach the nucleus and affect transcription (Figure 2i) [55]. The Ca²⁺-dependent transcription factors include the calcineurin B-controlled nuclear factor of activated T cells (NFAT), the cAMP response element-binding protein (CREB), the Ca²⁺-binding downstream regulatory element antagonist modulator (DREAM), and calsenilin [56]. Ca²⁺-binding proteins, such as calbindin D-28K, calretinin, and parvalbumin, are all important, allowing for rapid Ca²⁺ sequestration in the cytoplasm [57]. Although the nuclear Ca²⁺ concentration is controlled independently, compartmentalized Ca²⁺ signaling in the nucleus, as in associated organelles, is synchronized with changes in the cytosol [4,5]. Proteins that bind calcium ions within cells are suspected of inducing pathological effects via downstream or transcriptional pathways rather than by providing pathological causes themselves.

2.1.3. Restoration of Intracellular Ca²⁺ Concentration

Because Ca²⁺ is stored in the cell, the ER, Golgi apparatus, and mitochondria have specific mechanisms for releasing and refilling Ca²⁺. During the “off” phase, these mechanisms contribute to the shaping of the Ca²⁺ signal and the clearance of [Ca²⁺]i. Sarcoplasmic reticulum Ca²⁺ ATPase (SERCA) (Figure 2ii) removes cytosolic Ca²⁺ and pumps Ca²⁺ into the ER lumen, where it can be further sequestered by Ca²⁺-binding EF-hand proteins. The GTP-binding protein Gq11 is activated by glutamate via G protein-coupled receptors (GPCRs) in the plasma membrane and stimulates the release of the secondary messenger inositol triphosphate (IP3) by activating phospholipase C (PLC) [58]. Inositol 1,4,5-trisphosphate receptors (IP3Rs) (Figure 2ii) in the ER membrane release Ca²⁺ from the ER into the cytosol by binding to IP3 [59]. These IP3Rs are regulated by several factors, both in the cytosol and on the luminal surface of the ER, including apoptosis-related cytochrome C, apoptosis-related proteins of the B-cell lymphoma/leukemia-2 (Bcl-2) gene family, and Ca²⁺-binding proteins or Ca²⁺ itself [4].

Ryanodine receptors (RyRs) (Figure 2ii) are triggered by high [Ca²⁺]i levels to drive the further release of Ca²⁺ from the ER [60]. This mechanism, termed Ca²⁺-induced Ca²⁺ release (CICR), is a critical driver of [Ca²⁺]i increases [61]. In contrast to IP3Rs, RyRs are regulated by intracellular factors, such as cyclic adenosine diphosphate ribose (cADP-ribose) [62]. As [Ca²⁺]i increases, IP3Rs become sensitized to IP3, thereby initiating CICR progression, whereas low [Ca²⁺]i inhibits this pathway [63]. The CICR involving IP3Rs and RyRs is linked to the Ca²⁺ spark, opening of a single channel and an associated channel into Ca²⁺ waves, and coordinates the shaping of Ca²⁺ signaling and oscillations. These waves then propagate Ca²⁺ signals into the cytoplasm [4]. When the internal Ca²⁺ in the ER store is depleted, the ER refilling mechanism is triggered, thereby increasing Ca²⁺ influx through store-operated channels (SOCs) (Figure 1) in the plasma membrane, in a process termed capacitative Ca²⁺ entry (CCE) [63]. Recently, one possible mechanism of action of SOCs has been proposed, in which Stim1, a Ca²⁺-binding sensor in ER membranes, interacts with Orai1, a Ca²⁺ channel in plasma membranes. Upon Ca²⁺ depletion in the ER store, Stim1 aggregates to activate Orai1 to open the channel [4].

Mitochondria are generally located in close proximity to ER Ca²⁺ channels. The function of mitochondria to regulate intracellular calcium is vital for neuron survival [64]. This is because it influences various cellular processes, including energy production [65], reactive oxygen species generation [66], and apoptotic pathways [67]. In PD, the mitochondria malfunction, leading to higher intracellular calcium levels [68]. Furthermore, the impaired mitochondria in PD affect the endoplasmic reticulum–mitochondria calcium signaling [69,70], further destabilizing the cellular environment [71]. Mitochondrial Ca²⁺ sequestration and internalization are mediated by this uniporter, whereas Ca²⁺ release is mediated by exchanges with Na⁺ or H⁺ ions (Figure 2iii) [72]. To protect against excess [Ca²⁺]i, Ca²⁺ is sequestered by its influx of Ca²⁺ into the mitochondria [4,5]. Since mitochondria and ER are the major calcium ion storage spaces within cells, if their regulatory mechanisms break down, calcium ions in cells increase. Then, calcium ion-mediated downstream or transcription can be increased, thereby accelerating PD progression by crosstalk with pathological factors.

2.2. Role of α-Synuclein

Pathologically, the loss of the SNc is important in PD. Dopaminergic neurons in the SNc of patients contained inclusion bodies termed Lewy bodies (LBs) [73]. LB formation is a crucial driver of many PD symptoms and is driven by aggregated α-syn. Interestingly, aggregated forms of α-syn have also been found in the cerebrospinal fluid of patients with PD [11]. α-syn comprises 140 amino acids across three modular domains (Figure 3A) [74]. Monomeric α-syn is unstable and binds to lipids in a process mediated by the N-terminus, an amphipathic α-helix, and imperfect 11 amino acid repeats within conserved KTKEGV repeats [75]. The N-terminal residues show a strong binding preference for negatively charged membrane phospholipids. The ß-sheet, the central hydrophobic component, is a nonamyloid component (NAC) [76]. The C-terminus consists of negatively charged residues that can bind calcium and microtubule-associated protein 1 B and has structural and functional similarities to the small heat-shock protein [77,78]. In addition, C-terminal-truncated monomeric α-syn plays a critical role in fibrillation [79]. The NAC region interacts with other amyloidogenic polypeptides, including Aß, Htt, and prions. NAC regions have also been suggested to cause self-aggregation [80]. The multiplications of α-syn gene (SNCA) causes familial PD and hereditary early-onset PD [81]. Post-translational modification, including phosphorylation, nitration, and ubiquitination, of α-syn are critical in modulating aggregation [82]. However, the correlation between the pathological function of α-syn and the pathological mechanism of PD remain unclear. In general, it is believed that the protofibril and oligomeric forms of mutant α-syn are more neurotoxic than the fibril form [83]. Indeed, several studies have indicated that mature α-syn aggregates exert a neuroprotective function and are involved in cellular-protective processes, as dopaminergic neuron cells containing α-syn aggregates or LB are healthy and show less loss in brain regions rich in LBs [11]. However, mutant α-syn tends to form oligomers rather than fibrils, thereby contributing to dopaminergic neurodegeneration in PD [84].

Recently, studies have provided evidence to indicate that presynaptic α-syn is involved in a calcium-triggered membrane interaction and that the C-terminal acidic tail can bind to the membrane via Ca²⁺, forming structures called Ca²⁺ bridges. In this state, the ß-sheet conformation of α-syn plays a key role in aggregation [85]. When aggregated at the plasma membrane, mutant α-syn can form pore-like structures in the plasma membrane; these pore-like α-syn oligomers disturb Ca²⁺ permeability, thereby increasing [Ca²⁺]i and consequently driving neuronal toxicity [86,87]. The presence of Ca²⁺ facilitates the formation of α-Syn liquid droplets and accelerates amyloid aggregation, modulating protein phase separation [88]. Additionally, α-syn aggregates bind to SERCA, stimulating its activity, which is important, as reducing SERCA activity has been shown to be neuroprotective. These findings suggest that SERCA and downstream processes could be potential therapeutic targets for α-synucleinopathies [89]. Furthermore, some research has indicated a novel role of monomeric α-syn in stimulating calcium clearance in neurons through the activation of plasma membrane Ca²⁺-ATPase and its binding to synaptic vesicles, which could advance our understanding of α-synucleinopathies [78,90]. Together, these results indicate that α-syn may play a key role in Ca²⁺ dyshomeostasis (Figure 3B).

2.3. Role of Leucine-Rich Repeat Kinase 2 (LRRK2)

Leucine-rich repeat kinase 2 (LRRK2) is a multifunctional protein that plays a significant role in the pathogenesis of PD. LRRK2 mutations, which lead to increased kinase activity, are associated with PD development, which is thought to contribute to neurodegenerative processes by affecting several molecular pathways [91]. LRRK2 mutations are autosomal-dominant and account for a significant proportion of patients with PD; specifically, mutations in LRRK2 have been observed in 5–10% of patients with familial PD and approximately 1% of patients with sporadic PD [92]. The LRRK2 protein contains a complex domain with GTPase and kinase activities, which plays an important role in intracellular signal transduction (Figure 4A). In addition, LRRK2 mutations are concentrated in the GTPase and kinase regions, indicating that these two enzymes are important in the pathogenesis of PD [93]. Mutations in LRRK2, particularly the G2019S mutation, are the most common genetic cause of familial and sporadic PD. Prior studies have shown that the G2019S mutation can cause neuronal degeneration by increasing kinase activity, providing important clues for understanding the pathological mechanisms of PD [94]. LRRK2 is also known to be involved in a variety of cellular processes, including membrane trafficking, mitochondrial function, autophagy–lysosomal pathways, cellular senescence, and neuroinflammation [14,15,95].

A previous study revealed that both wild-type and mutant LRRK2 G2019S increased Ca²⁺ current density and altered the activation properties of CaV2.1 channels [96]. This effect was reversed through treatment with an LRRK2 inhibitor, indicating a direct impact of LRRK2 kinase activity on channel function. Additionally, LRRK2 influences other VGCCs, suggesting a broader regulatory role [97]. Mutant LRRK2 G2019S or R1441C enhances mitochondrial calcium uptake, potentially contributing to neuronal damage [15]. LRRK2 mutations also upregulate the genes involved in mitochondrial calcium transport, which is mediated by the ERK1/2 pathway [98]. The modulation of mitochondrial calcium transport may offer a therapeutic strategy to mitigate the neuronal damage caused by mutant LRRK2. Moreover, VGCC dysfunction in VGCCs has been observed in dopaminergic neurons in PD models, highlighting a potential target for intervention to protect against neuronal loss (Figure 4B).

Research has indicated that targeting LRRK2 activity could be a therapeutic strategy, as it can help normalize the altered cellular processes associated with PD. Understanding the cellular mechanisms of LRRK2 in health and disease is crucial for developing targeted treatments that could potentially slow or halt the progression of PD. Studies continue to explore the role of LRRK2 to further elucidate its role in PD and identify additional therapeutic targets, with a particular focus on its role in astrocytes [99,100], which support neuronal health.

3. Conclusions

Several recent studies have indicated that Ca²⁺ dyshomeostasis can cause acute and chronic CNS diseases [1]. Abnormal Ca²⁺ concentrations lead to excitotoxicity, which may be important in neurodegenerative diseases [101]. The relationship between excitotoxicity and the progression of neuronal death can be mediated via the disruption of Ca²⁺ permeability and regulation [102]. Furthermore, neurodegenerative diseases tend to increase intracellular Ca²⁺ levels [103]. The increases in Ca²⁺ concentration in the cytosolic space promote oxidative phosphorylation, reactive oxygen species (ROS) generation, and mtDNA or protein damage [104]. Ca²⁺ signals can further activate severe toxic mechanisms including apoptosis [5]. These mechanisms are toxic to neuronal cells and can lead to cell death. Ca²⁺-mediated NO production is believed to contribute to the death of dopaminergic neurons in PD [105]. Dopaminergic neurons that express relatively high levels of the Ca²⁺-binding proteins calbindin and calretinin appear to be resistant to degeneration in PD [5,106].

In patients with PD, Ca²⁺ concentrations are important for the pacemaking of dopaminergic neurons in the SNc. Ca²⁺ influx occurs through Cav1.3/L-type channels, AMPARs, and NMDARs [37,107]. Increased Ca²⁺ concentrations lead to the loss of dopaminergic neurons, as α-syn aggregates form pore-like structures which increase Ca²⁺ permeability [108]. In addition, Ca²⁺ enhances the binding of α-syn to the plasma membrane [87]. These results suggest that the neurotoxic effects of α-syn are associated with Ca²⁺-dependent mechanisms. While the exact pathways underlying α-syn-associated excitotoxicity are still unclear, α-syn-induced dopaminergic neuron death is likely related to Ca²⁺ concentrations. Mutant LRRK2 has been found to increase mitochondrial calcium uptake, leading to the transcriptional upregulation of proteins involved in mitochondrial calcium handling [15,98]. Inhibition of these pathways can protect against neurite shortening caused by mutant LRRK2 [97]. Mutations in LRRK2 can further impair mitochondrial Ca²⁺ extrusion, contributing to mitochondrial dysfunction and cell death in PD [96]. Overall, targeting mitochondrial calcium handling may be a potential therapeutic strategy for the treatment of PD. The research to date has confirmed the effects of α-syn and LRRK2 mutations in Ca²⁺ dyshomeostasis among PD pathologies, which will have important implications for future research and treatment development. These findings will improve our understanding of the basic biology of α-syn and LRRK2 and may further provide insights that could lead to new strategies underlying effective PD diagnosis and therapy. The involvement of α-syn or LRRK2 in PD pathology is clinically heterogeneous, meaning that symptoms and rates of progression vary among patients. As such, an individualized approach to PD patients with α-synucleinopathy and LRRK2 mutations may be required to ensure accurate diagnosis and effective treatment planning.

Author Contributions

Conceptualization: D.H.H.; methodology: D.H.H.; investigation: D.H.H., D.N. and H.K.; resources: S.J.H.; funding acquisition: D.H.H.; data curation: S.J.H.; writing—original draft preparation: D.H.H.; writing—review and editing: I.S.; visualization: D.H.H.; supervision: I.S.; and project administration: D.H.H. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Conflicts of Interest

The authors declare no conflicts of interest.

Footnotes

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Figures

Figure 1. The protein machinery involved in the regulation of Ca2+ via the plasma membrane. It schematically summarizes the uptake and release of Ca2+ through components in the plasma membrane.

Figure 2. Schematic illustration of cellular mechanisms involved in Ca2+ signals and restoration, including the following 3 compartments: (i) the cellular responses to Ca2+ in neurons via Ca2+-binding and -sensing molecules, (ii) the ER-mediated modulation of Ca2+ homeostasis, and (iii) the restoration of Ca2+ by the mitochondria.

Figure 3. The structure and calcium-mediated PD pathomechanism involving α-syn (A). Monomeric α-syn is related to (i) Ca2+-ATPase activities and (ii) the presynaptic docking of synaptic vesicles. (iii) α-syn can form oligomers through calcium binding and is anchored to the intact plasma membrane through the calcium bridge effect. (iv) Moreover, aggregates of α-syn can disrupt Ca2+ restoration in the ER via binding to SERCA (B).

Figure 4. The structure of LRRK2 and its role in calcium dyshomeostasis (A). Enhanced LRRK2 kinase activity can alter (i) the activity of CaV2.1 channels, (ii) L- or P-type VGCCs, and (iii) Ca2+ restoration in the mitochondria (B).

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