Platelets and the Role of P2X Receptors in Nociception,Pain, Neuronal Toxicity and Thromboinflammation

P2X receptors belong to a family of cation channel proteins, which respond to extracellular adenosine 5′-triphosphate (ATP). These receptors have gained increasing attention in basic and translational research, as they are central to a variety of important pathophysiological processes such as the modulation of cardiovascular physiology, mediation of nociception, platelet and macrophage activation, or neuronal–glial integration. While P2X1 receptor activation is long known to drive platelet aggregation, P2X7 receptor antagonists have recently been reported to inhibit platelet activation. Considering the role of both P2X receptors and platelet-mediated inflammation in neuronal diseases such as multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, and stroke, targeting purinergic receptors may provide a valuable novel therapeutic approach in these diseases. Therefore, the present review illuminates the role of platelets and purinergic signaling in these neurological conditions to evaluate potential translational implications.     

The Bacterial Amyloids Phenol Soluble Modulins from Staphylococcus aureus Catalyze Alpha-Synuclein Aggregation

Aggregated α-synuclein (α-syn) is the main constituent of Lewy bodies, which are a pathological hallmark of Parkinson’s disease (PD). Environmental factors are thought to be potential triggers capable of initiating the aggregation of the otherwise monomeric α-syn. Braak’s seminal work redirected attention to the intestine and recent reports of dysbiosis have highlighted the potential causative role of the microbiome in the initiation of pathology of PD. Staphylococcus aureus is a bacterium carried by 30–70% of the general population. It has been shown to produce functional amyloids, called phenol soluble modulins (PSMαs). Here, we studied the kinetics of α-syn aggregation under quiescent conditions in the presence or absence of four different PSMα peptides and observed a remarkable shortening of the lag phase in their presence. Whereas pure α-syn monomer did not aggregate up to 450 h after initiation of the experiment in neither neutral nor mildly acidic buffer, the addition of different PSMα peptides resulted in an almost immediate increase in the Thioflavin T (ThT) fluorescence. Despite similar peptide sequences, the different PSMα peptides displayed distinct effects on the kinetics of α-syn aggregation. Kinetic analyses of the data suggest that all four peptides catalyze α-syn aggregation through heterogeneous primary nucleation. The immunogold electron microscopic analyses showed that the aggregates were fibrillar and composed of α-syn. In addition of the co-aggregated materials to a cell model expressing the A53T α-syn variant fused to GFP was found to catalyze α-syn aggregation and phosphorylation in the cells. Our results provide evidence of a potential trigger of synucleinopathies and could have implications for the prevention of the diseases.     

Benzyl Isothiocyanate Attenuates Inflammasome Activation in Pseudomonas aeruginosa LPS-Stimulated THP-1 Cells and Exerts Regulation through the MAPKs/NF-κB Pathway

Inflammasomes are a group of intracellular multiprotein platforms that play important roles in immune systems. Benzyl isothiocyanate (BITC) is a constituent of cruciferous plants and has been confirmed to exhibit various biological activities. The modulatory effects of BITC on inflammasome-mediated interleukin (IL)-1β expression and its regulatory mechanisms in Pseudomonas aeruginosa (P. aeruginosa) LPS/ATP-stimulated THP-1 cells was investigated. Monocytic THP-1 cells were treated with phorbol myristate acetate (PMA) to induce differentiation into macrophages. Enzyme-linked immunosorbent assays (ELISA) were performed to measure the levels of IL-1β produced in P. aeruginosa LPS/ATP-exposed THP-1 cells. Western blotting was performed to examine the BITC modulatory mechanisms in inflammasome-mediated signaling pathways. BITC inhibited IL-1β production in P. aeruginosa LPS/ATP-induced THP-1 cells. BITC also inhibited activation of leucine-rich repeat protein-3 (NLRP3) and caspase-1 in P. aeruginosa LPS/ATP-induced THP-1 cells. Furthermore, we show that mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) activation in P. aeruginosa LPS was attenuated by BITC. These BITC-mediated modulatory effects on IL-1β production may have therapeutic potential for inflammasome-mediated disorders such as a nasal polyp.     

Decrease in ITGA7 Levels Is Associated with an Increase in α-Synuclein Levels in an MPTP-Induced Parkinson’s Disease Mouse Model and SH-SY5Y Cells

We investigated the potential association between integrin α7 (ITGA7) and alpha-synuclein (α-syn) in a methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson’s disease (PD) mouse model. Tyrosine hydroxylase (TH), ITGA7, and α-syn expression in the substantia nigra (SN) of the brain were observed to examine the pathological characteristics of PD. To determine the relationship between ITGA7 and PD, the expression of TH and α-syn was investigated after ITGA7 siRNA knockdown in SH-SY5Y cells. The ITGA7 microarray signal was decreased in the SN of the MPTP group, indicating reduced ITGA7 expression compared to that in the control. The expression patterns of ITGA7 in the control group and those of α-syn in the MPTP group were similar on immunohistochemical staining. Reduction in ITGA7 expression by ITGA7 siRNA administration induced a decrease in TH expression and an increase in α-syn expression in SH-SY5Y cells. The decreased expression of ITGA7 significantly decreased the expression of bcl2 and increased the bax/bcl2 ratio in SH-SY5Y cells. These results suggest that reduced ITGA7 expression may be related to increased α-syn expression and apoptosis of dopaminergic cells in an MPTP-induced PD mouse model. To the best of our knowledge, this is the first study to show an association between ITGA7 and PD.     

A Novel NOX Inhibitor Treatment Attenuates Parkinson’s Disease-Related Pathology in Mouse Models

Parkinson’s disease (PD) is a progressive neurodegenerative motor disorder without an available therapeutic to halt the formation of Lewy bodies for preventing dopaminergic neuronal loss in the nigrostriatal pathway. Since oxidative-stress-mediated damage has been commonly reported as one of the main pathological mechanisms in PD, we assessed the efficacy of a novel NOX inhibitor from AptaBio Therapeutics (C-6) in dopaminergic cells and PD mouse models. The compound reduced the cytotoxicity and enhanced the cell viability at various concentrations against MPP+ and α-synuclein preformed fibrils (PFFs). Further, the levels of ROS and protein aggregation were significantly reduced at the optimal concentration (1 µM). Using two different mouse models, we gavaged C-6 at two different doses to the PD sign-displaying transgenic mice for 2 weeks and stereotaxically PFF-injected mice for 5 weeks. Our results demonstrated that both C-6-treated mouse models showed alleviated motor deficits in pole test, hindlimb clasping, crossbeam, rotarod, grooming, and nesting analyses. We also confirmed that the compound treatment reduced the levels of protein aggregation, along with phosphorylated-α-synuclein, in the striatum and ventral midbrain and further dopaminergic neuronal loss. Taken together, our results strongly suggest that NOX inhibition can be a potential therapeutic target for PD.     

PARK7/DJ-1 as a Therapeutic Target in Gut-Brain Axis Diseases

It is increasingly known that Parkinson’s (PD) and Alzheimer’s (AD) diseases occur more frequently in patients with inflammatory gastrointestinal diseases including inflammatory bowel (IBD) or celiac disease, indicating a pathological link between them. Although epidemiological observations suggest the existence of the gut-brain axis (GBA) involving systemic inflammatory and neural pathways, little is known about the exact molecular mechanisms. Parkinson’s disease 7 (PARK7/DJ-1) is a multifunctional protein whose protective role has been widely demonstrated in neurodegenerative diseases, including PD, AD, or ischemic stroke. Recent studies also revealed the importance of PARK7/DJ-1 in the maintenance of the gut microbiome and also in the regulation of intestinal inflammation. All these findings suggest that PARK7/DJ-1 may be a link and also a potential therapeutic target in gut and brain diseases. In this review, therefore, we discuss our current knowledge about PARK7/DJ-1 in the context of GBA diseases.     

Glitazone Treatment Rescues Phenotypic Deficits in a Fly Model of Gaucher/Parkinson’s Disease

Parkinson’s Disease (PD) is the most common movement disorder, and the strongest genetic risk factor for PD is mutations in the glucocerebrosidase gene (GBA). Mutations in GBA also lead to the development of Gaucher Disease (GD), the most common type of lysosomal storage disorder. Current therapeutic approaches fail to address neurological GD symptoms. Therefore, identifying therapeutic strategies that improve the phenotypic traits associated with GD/PD in animal models may provide an opportunity for treating neurological manifestations of GD/PD. Thiazolidinediones (TZDs, also called glitazones) are a class of compounds targeted for the treatment of type 2 diabetes, and have also shown promise for the treatment of neurodegenerative disease, including PD. Here, we tested the efficacy of glitazone administration during development in a fly GD model with deletions in the GBA homolog, dGBA1b (GBA1^ΔTT/ΔTT). We observed an optimal dose of pioglitazone (PGZ) at a concentration of 1 μM that reduced sleep deficits, locomotor impairments, climbing defects, and restoration of normal protein levels of Ref(2)P, a marker of autophagic flux, in GBA1^ΔTT/ΔTT mutant flies, compared to GBA1^+/+ control flies. These data suggest that PGZ may represent a potential compound with which to treat GD/PD by improving function of lysosomal-autophagy pathways, a cellular process that removes misfolded or aggregated proteins.     

Anti-Inflammatory Effect of IKK-Activated GSK-3β Inhibitory Peptide Prevented Nigrostriatal Neurodegeneration in the Rodent Model of Parkinson’s Disease

Parkinson’s disease (PD) is a progressive movement disorder caused by nigrostriatal neurodegeneration. Since chronically activated neuroinflammation accelerates neurodegeneration in PD, we considered that modulating chronic neuroinflammatory response might provide a novel therapeutic approach. Glycogen synthase kinase 3 (GSK-3) is a multifunctional serine/threonine protein kinase with two isoforms, GSK-3α and GSK-3β, and GSK-3β plays crucial roles in inflammatory response, which include microglial migration and peripheral immune cell activation. GSK-3β inhibitory peptide (IAGIP) is specifically activated by activated inhibitory kappa B kinase (IKK), and its therapeutic effects have been demonstrated in a mouse model of colitis. Here, we investigated whether the anti-inflammatory effects of IAGIP prevent neurodegeneration in the rodent model of PD. IAGIP significantly reduced MPP⁺-induced astrocyte activation and inflammatory response in primary astrocytes without affecting the phosphorylations of ERK or JNK. In addition, IAGIP inhibited LPS-induced cell migration and p65 activation in BV-2 microglial cells. In vivo study using an MPTP-induced mouse model of PD revealed that intravenous IAGIP effectively prevented motor dysfunction and nigrostriatal neurodegeneration. Our findings suggest that IAGIP has a curative potential in PD models and could offer new therapeutic possibilities for targeting PD.     

Effects of the Toxic Metals Arsenite and Cadmium on α-Synuclein Aggregation In Vitro and in Cells

Exposure to heavy metals, including arsenic and cadmium, is associated with neurodegenerative disorders such as Parkinson’s disease. However, the mechanistic details of how these metals contribute to pathogenesis are not well understood. To search for underlying mechanisms involving α-synuclein, the protein that forms amyloids in Parkinson’s disease, we here assessed the effects of arsenic and cadmium on α-synuclein amyloid formation in vitro and in Saccharomyces cerevisiae (budding yeast) cells. Atomic force microscopy experiments with acetylated human α-synuclein demonstrated that amyloid fibers formed in the presence of the metals have a different fiber pitch compared to those formed without metals. Both metal ions become incorporated into the amyloid fibers, and cadmium also accelerated the nucleation step in the amyloid formation process, likely via binding to intermediate species. Fluorescence microscopy analyses of yeast cells expressing fluorescently tagged α-synuclein demonstrated that arsenic and cadmium affected the distribution of α-synuclein aggregates within the cells, reduced aggregate clearance, and aggravated α-synuclein toxicity. Taken together, our in vitro data demonstrate that interactions between these two metals and α-synuclein modulate the resulting amyloid fiber structures, which, in turn, might relate to the observed effects in the yeast cells. Whilst our study advances our understanding of how these metals affect α-synuclein biophysics, further in vitro characterization as well as human cell studies are desired to fully appreciate their role in the progression of Parkinson’s disease.     

Is Chelation Therapy a Potential Treatment for Parkinson’s Disease?

Iron loading in some brain regions occurs in Parkinson’s Disease (PD), and it has been considered that its removal by iron chelators could be an appropriate therapeutic approach. Since neuroinflammation with microgliosis is also a common feature of PD, it is possible that iron is sequestered within cells as a result of the “anaemia of chronic disease” and remains unavailable to the chelator. In this review, the extent of neuroinflammation in PD is discussed together with the role played by glia cells, specifically microglia and astrocytes, in controlling iron metabolism during inflammation, together with the results of MRI studies. The current use of chelators in clinical medicine is presented together with a discussion of two clinical trials of PD patients where an iron chelator was administered and showed encouraging results. It is proposed that the use of anti-inflammatory drugs combined with an iron chelator might be a better approach to increase chelator efficacy.     

Immunogenicity of MultiTEP-Platform-Based Recombinant Protein Vaccine,PV-1950R,Targeting Three B-Cell Antigenic Determinants of Pathological α-Synuclein

Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are characterized by the aberrant accumulation of intracytoplasmic misfolded and aggregated α-synuclein (α-Syn), resulting in neurodegeneration associated with inflammation. The propagation of α-Syn aggregates from cell to cell is implicated in the spreading of pathological α-Syn in the brain and disease progression. We and others demonstrated that antibodies generated after active and passive vaccinations could inhibit the propagation of pathological α-Syn in the extracellular space and prevent/inhibit disease/s in the relevant animal models. We recently tested the immunogenicity and efficacy of four DNA vaccines on the basis of the universal MultiTEP platform technology in the DLB/PD mouse model. The antibodies generated by these vaccines efficiently reduced/inhibited the accumulation of pathological α-Syn in the different brain regions and improved the motor deficit of immunized female mice. The most immunogenic and preclinically effective vaccine, PV-1950D, targeting three B-cell epitopes of pathological α-Syn simultaneously, has been selected for future IND-enabling studies. However, to ensure therapeutically potent concentrations of α-Syn antibodies in the periphery of the vaccinated elderly, we developed a recombinant protein-based MultiTEP vaccine, PV-1950R/A, and tested its immunogenicity in young and aged D-line mice. Antibody responses induced by immunizations with the PV-1950R/A vaccine and its homologous DNA counterpart, PV-1950D, in a mouse model of PD/DLB have been compared.     

Transcriptional Regulation of the Synaptic Vesicle Protein Synaptogyrin-3 (SYNGR3) Gene: The Effects of NURR1 on Its Expression

Synaptogyrin-3 (SYNGR3) is a synaptic vesicular membrane protein. Amongst four homologues (SYNGR1 to 4), SYNGR1 and 3 are especially abundant in the brain. SYNGR3 interacts with the dopamine transporter (DAT) to facilitate dopamine (DA) uptake and synaptic DA turnover in dopaminergic transmission. Perturbed SYNGR3 expression is observed in Parkinson’s disease (PD). The regulatory elements which affect SYNGR3 expression are unknown. Nuclear-receptor-related-1 protein (NURR1) can regulate dopaminergic neuronal differentiation and maintenance via binding to NGFI-B response elements (NBRE). We explored whether NURR1 can regulate SYNGR3 expression using an in silico analysis of the 5′-flanking region of the human SYNGR3 gene, reporter gene activity and an electrophoretic mobility shift assay (EMSA) of potential cis-acting sites. In silico analysis of two genomic DNA segments (1870 bp 5′-flanking region and 1870 + 159 bp of first exon) revealed one X Core Promoter Element 1 (XCPE1), two SP1, and three potential non-canonical NBRE response elements (ncNBRE) but no CAAT or TATA box. The longer segment exhibited gene promoter activity in luciferase reporter assays. Site-directed mutagenesis of XCPE1 decreased promoter activity in human neuroblastoma SH-SY5Y (↓43.2%) and human embryonic kidney HEK293 cells (↓39.7%). EMSA demonstrated NURR1 binding to these three ncNBRE. Site-directed mutagenesis of these ncNBRE reduced promoter activity by 11–17% in SH-SY5Y (neuronal) but not in HEK293 (non-neuronal) cells. C-DIM12 (Nurr1 activator) increased SYNGR3 protein expression in SH-SY5Y cells and its promoter activity using a real-time luciferase assay. As perturbed vesicular function is a feature of major neurodegenerative diseases, inducing SYNGR3 expression by NURR1 activators may be a potential therapeutic target to attenuate synaptic dysfunction in PD.     

A Pilot Study of Changes in the Level of Catecholamines and the Activity of α-2-Macroglobulin in the Tear Fluid of Patients with Parkinson’s Disease and Parkinsonian Mice

Development of differential and early (preclinical) diagnostics of Parkinson’s disease (PD) is among the priorities in neuroscience. We searched for changes in the level of catecholamines and α-2-macroglobulin activity in the tear fluid (TF) in PD patients at an early clinical stage. It was shown that TF in patients is characterized by an increased level of noradrenaline mainly on the ipsilateral side of pronounced motor symptoms (72%, p = 0.049), a decreased level of adrenaline on both sides (ipsilateral—53%, p = 0.004; contralateral—42%, p = 0.02), and an increased α-2-macroglobulin activity on both sides (ipsilateral—53%, p = 0.03; contralateral—56%, p = 0.037) compared to controls. These changes are considered as potential biomarkers for differential diagnosis. Similar changes in the TF were found in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice when modeling clinical and preclinical stages of PD. These data show the adequacy of models to the pathogenesis of PD along the selected metabolic pathways, and also suggest that the found TF changes can be considered as potential biomarkers for preclinical diagnosis of PD. In Parkinsonian mice, the level of catecholamines also changes in the lacrimal glands, which makes it possible to consider them as one of the sources of catecholamines in the TF.     

A Novel LRRK2 Variant p.G2294R in the WD40 Domain Identified in Familial Parkinson’s Disease Affects LRRK2 Protein Levels

Leucine-rich repeat kinase 2 (LRRK2) is a major causative gene of late-onset familial Parkinson’s disease (PD). The suppression of kinase activity is believed to confer neuroprotection, as most pathogenic variants of LRRK2 associated with PD exhibit increased kinase activity. We herein report a novel LRRK2 variant—p.G2294R—located in the WD40 domain, detected through targeted gene-panel screening in a patient with familial PD. The proband showed late-onset Parkinsonism with dysautonomia and a good response to levodopa, without cognitive decline or psychosis. Cultured cell experiments revealed that p.G2294R is highly destabilized at the protein level. The LRRK2 p.G2294R protein expression was upregulated in the patient’s peripheral blood lymphocytes. However, macrophages differentiated from the same peripheral blood showed decreased LRRK2 protein levels. Moreover, our experiment indicated reduced phagocytic activity in the pathogenic yeasts and α-synuclein fibrils. This PD case presents an example wherein the decrease in LRRK2 activity did not act in a neuroprotective manner. Further investigations are needed in order to elucidate the relationship between LRRK2 expression in the central nervous system and the pathogenesis caused by altered LRRK2 activity.     

Germinated Rhynchosia nulubilis Fermented with Lactobacillus pentosus SC65 Reduces Particulate Matter Induced Type II Alveolar Epithelial Apoptotic Cell Death

Particulate matter (PM) is a significant environmental pollutant that promotes respiratory diseases, including lung injury and inflammation, by inducing oxidative stress. Rhynchosia nulubilis (black soybean) is traditionally used to prevent chronic respiratory disease via inducing antioxidant and anti-inflammatory effects. To investigate the effects of Lactobacillus pentosus SC65 fermented GR (GR-SC65) and Pediococcus pentosaceus ON81A (GR-ON81A) against PM-induced oxidative stress and cell death in A549 cells, we performed the 2-7-dichlorodihydrofluorescein diacetate and cell counting kit-8 assays, as well as Hoechst 33342 and propidium iodide staining and western blotting. GR-SC65 showed the highest total polyphenolic contents and 1,1-diphenyl-2-picrylidrazil radical scavenging activity among lactic acid bacteria-fermented GRs (p < 0.001 vs. GR). Four soy peptides, β-conglycinin breakdowns (INAENNQRNF, ISSEDKPFN, LAFPGSAQAVEK, and LAFPGSAKDIEN), were detected in GR-SC65, but not in GR. In GR-SC65, PM-induced A549 cell death was less than that observed in GR-ON81A and GR (p < 0.001 vs. PM-treated group). GR-SC65 significantly decreased intracellular reactive oxidative species (ROS) when compared with PM (*** p < 0.001 vs. PM). GR-SC65 decreased the levels of BAX, active caspase-9, -3, and poly ADP-ribose polymerase (PARP) proteins (^# p < 0.01, ^### p < 0.001 vs. PM), while increasing the level of BCL-2 protein, a mitochondrial anti-apoptotic protein (^### p < 0.001 vs. PM). Our findings indicate that GR-SC65 inhibited PM-induced cell death by suppressing the levels of ROS, active caspase-9 and -3, and PARP proteins, while enhancing the level of BCL-2 protein in type II alveolar epithelial A549 cells. Therefore, GR-SC65 might be a potential therapeutic and preventive agent against PM-induced lung injury.     

Srpk3 Decrease Associated with Alpha-Synuclein Increase in Muscles of MPTP-Induced Parkinson’s Disease Mice

Parkinson’s disease (PD) is characterized by a loss of dopaminergic cells in the substantia nigra, and its histopathological features include the presence of fibrillar aggregates of α-synuclein (α-syn), which are called Lewy bodies and Lewy neurites. Lewy pathology has been identified not only in the brain but also in various tissues, including muscles. This study aimed to investigate the link between serine/arginine-rich protein specific kinase 3 (srpk3) and α-syn in muscles in PD. We conducted experiments on the quadriceps femoris of a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model and the C2C12 cell line after treatment with 1-methyl-4-phenylpyridinium (MPP+) and srpk3 short interfering RNA (siRNA). Compared to the control group, the MPTP group showed significantly reduced expression of srpk3, but increased expression of α-syn. In MPP+-treated C2C12 cells, srpk3 expression gradually decreased and α-syn expression increased with the increasing MPP+ concentration. Moreover, experiments in C2C12 cells using srpk3 siRNA showed increased expressions of α-syn and phosphorylated α-syn. Our results showed that srpk3 expression could be altered by MPTP intoxication in muscles, and this change may be related to changes in α-syn expression. Furthermore, this study could contribute to advancement of research on the mechanism by which srpk3 plays a role in PD.     

Novel Redox-Dependent Esterase Activity (EC 3.1.1.2) for DJ-1: Implications for Parkinson’s Disease

Mutations the in human DJ-1 (hDJ-1) gene are associated with early-onset autosomal recessive forms of Parkinson’s disease (PD). hDJ-1/parkinsonism associated deglycase (PARK7) is a cytoprotective multi-functional protein that contains a conserved cysteine-protease domain. Given that cysteine-proteases can act on both amide and ester substrates, we surmised that hDJ-1 possessed cysteine-mediated esterase activity. To test this hypothesis, hDJ-1 was overexpressed, purified and tested for activity towards 4-nitrophenyl acetate (pNPA) as µmol of pNPA hydrolyzed/min/mg·protein (U/mg protein). hDJ-1 showed maximum reaction velocity esterase activity (V_max = 235.10 ± 12.00 U/mg protein), with a sigmoidal fit (S_0.5 = 0.55 ± 0.040 mM) and apparent positive cooperativity (Hill coefficient of 2.05 ± 0.28). A PD-associated mutant of DJ-1 (M26I) lacked activity. Unlike its protease activity which is inactivated by reactive oxygen species (ROS), esterase activity of hDJ-1 is enhanced upon exposure to low concentrations of hydrogen peroxide (<10 µM) and plateaus at elevated concentrations (>100 µM) suggesting that its activity is resistant to oxidative stress. Esterase activity of DJ-1 requires oxidation of catalytic cysteines, as chemically protecting cysteines blocked its activity whereas an oxido-mimetic mutant of DJ-1 (C106D) exhibited robust esterase activity. Molecular docking studies suggest that C106 and L126 within its catalytic site interact with esterase substrates. Overall, our data show that hDJ-1 contains intrinsic redox-sensitive esterase activity that is abolished in a PD-associated mutant form of the hDJ-1 protein.     

Genes Implicated in Familial Parkinson’s Disease Provide a Dual Picture of Nigral Dopaminergic Neurodegeneration with Mitochondria Taking Center Stage

The mechanism of nigral dopaminergic neuronal degeneration in Parkinson’s disease (PD) is unknown. One of the pathological characteristics of the disease is the deposition of α-synuclein (α-syn) that occurs in the brain from both familial and sporadic PD patients. This paper constitutes a narrative review that takes advantage of information related to genes (SNCA, LRRK2, GBA, UCHL1, VPS35, PRKN, PINK1, ATP13A2, PLA2G6, DNAJC6, SYNJ1, DJ-1/PARK7 and FBXO7) involved in familial cases of Parkinson’s disease (PD) to explore their usefulness in deciphering the origin of dopaminergic denervation in many types of PD. Direct or functional interactions between genes or gene products are evaluated using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. The rationale is to propose a map of the interactions between SNCA, the gene encoding for α-syn that aggregates in PD, and other genes, the mutations of which lead to early-onset PD. The map contrasts with the findings obtained using animal models that are the knockout of one of those genes or that express the mutated human gene. From combining in silico data from STRING-based assays with in vitro and in vivo data in transgenic animals, two likely mechanisms appeared: (i) the processing of native α-syn is altered due to the mutation of genes involved in vesicular trafficking and protein processing, or (ii) α-syn mutants alter the mechanisms necessary for the correct vesicular trafficking and protein processing. Mitochondria are a common denominator since both mechanisms require extra energy production, and the energy for the survival of neurons is obtained mainly from the complete oxidation of glucose. Dopamine itself can result in an additional burden to the mitochondria of dopaminergic neurons because its handling produces free radicals. Drugs acting on G protein-coupled receptors (GPCRs) in the mitochondria of neurons may hopefully end up targeting those receptors to reduce oxidative burden and increase mitochondrial performance. In summary, the analysis of the data of genes related to familial PD provides relevant information on the etiology of sporadic cases and might suggest new therapeutic approaches.