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12 pages, 1059 KiB

Open AccessArticle

A Next-Generation Sequencing Study in a Cohort of Sicilian Patients with Parkinson’s Disease

by Michele Salemi, Giuseppe Lanza, Maria Grazia Salluzzo, Francesca A. Schillaci, Francesco Domenico Di Blasi, Angela Cordella, Salvatore Caniglia, Bartolo Lanuzza, Manuela Morreale, Pietro Marano, Mariangela Tripodi and Raffaele Ferri

Biomedicines 2023, 11(12), 3118; https://doi.org/10.3390/biomedicines11123118 - 22 Nov 2023

Viewed by 953

Abstract

Parkinson’s disease (PD) is a multisystem and multifactorial disorder and, therefore, the application of modern genetic techniques may assist in unraveling its complex pathophysiology. We conducted a clinical–demographic evaluation of 126 patients with PD, all of whom were Caucasian and of Sicilian ancestry. [...] Read more.

Parkinson’s disease (PD) is a multisystem and multifactorial disorder and, therefore, the application of modern genetic techniques may assist in unraveling its complex pathophysiology. We conducted a clinical–demographic evaluation of 126 patients with PD, all of whom were Caucasian and of Sicilian ancestry. DNA was extracted from the peripheral blood for each patient, followed by sequencing using a Next-Generation Sequencing system. This system was based on a custom gene panel comprising 162 genes. The sample underwent further filtering, taking into account the allele frequencies of genetic variants, their presence in the Human Gene Mutation Database, and their association in the literature with PD or other movement/neurodegenerative disorders. The largest number of variants was identified in the leucine-rich repeat kinase 2 (LRRK2) gene. However, variants in other genes, such as acid beta-glucosidase (GBA), DNA polymerase gamma catalytic subunit (POLG), and parkin RBR E3 ubiquitin protein ligase (PRKN), were also discovered. Interestingly, some of these variants had not been previously associated with PD. Enhancing our understanding of the genetic basis of PD and identifying new variants possibly linked to the disease will contribute to improved diagnostic accuracy, therapeutic developments, and prognostic insights for affected individuals. Full article

(This article belongs to the Special Issue Parkinson’s Disease: From Pathophysiology to Novel Therapeutic Approaches)

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31 pages, 15089 KiB

Open AccessArticle

Unravelling the Molecular Mechanisms of a Quercetin Nanocrystal for Treating Potential Parkinson’s Disease in a Rotenone Model: Supporting Evidence of Network Pharmacology and In Silico Data Analysis

by Yeruva Sai Lakshmi, D. S. N. B. K. Prasanth, Karumuri Taraka Sunil Kumar, Sheikh F. Ahmad, Seemaladinne Ramanjaneyulu, Nalluri Rahul and Praveen Kumar Pasala

Biomedicines 2023, 11(10), 2756; https://doi.org/10.3390/biomedicines11102756 - 11 Oct 2023

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Abstract

The prevalence of Parkinson’s disease places a significant burden on society; therefore, there is an urgent need to develop more effective drugs. However, the development of these drugs is both expensive and risky. Quercetin (QUE) has potent pharmacological effects on neurodegenerative diseases, but [...] Read more.

The prevalence of Parkinson’s disease places a significant burden on society; therefore, there is an urgent need to develop more effective drugs. However, the development of these drugs is both expensive and risky. Quercetin (QUE) has potent pharmacological effects on neurodegenerative diseases, but its low solubility in water and poor bioavailability limit its use in pharmaceutical applications. In this study, Quercetin nanocrystals (QNC) were synthesized and compared to standard QUE. A network-pharmacology-based methodology was applied, including target prediction, network construction, a gene ontology (GO) analysis, a KEGG pathway enrichment analysis, and molecular docking. This study aimed to identify the targets of QUE relevant to the treatment of Parkinson’s disease and investigate the associated pharmacological mechanisms. Most of the predicted targets are involved in dopamine uptake during synaptic transmission. QUE regulates the key targets DRD2 and DRD4, which significantly affect dopaminergic synapses. The molecular docking results showed that QUE had a better binding affinity than the standard drug l-Dopa. From these experiments, it can be concluded that QNC effectively reduced the adverse effects caused by rotenone-induced oxidative stress in biochemical, neurochemical, and histopathological alterations. Therefore, QNC can potentially treat Parkinson’s disease, and its effectiveness should be assessed in future clinical trials. Full article

(This article belongs to the Special Issue Parkinson’s Disease: From Pathophysiology to Novel Therapeutic Approaches)

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10 pages, 933 KiB

Open AccessArticle

Investigation of PRKN Mutations in Levodopa-Induced Dyskinesia in Parkinson’s Disease Treatment

by Ana Gabrielle Bispo, Caio S. Silva, Camille Sena-dos-Santos, Dafne Dalledone Moura, Brenda Hanae Bentes Koshimoto, Bruno Lopes Santos-Lobato, Ândrea Ribeiro-dos-Santos and Giovanna C. Cavalcante

Biomedicines 2023, 11(8), 2230; https://doi.org/10.3390/biomedicines11082230 - 09 Aug 2023

Viewed by 918

Abstract

Mitophagy is an important process that participates in mitochondrial quality control. Dysfunctions in this process can be caused by mutations in genes like PRKN and are associated with the development and progression of Parkinson’s Disease (PD). The most used drug in the treatment [...] Read more.

Mitophagy is an important process that participates in mitochondrial quality control. Dysfunctions in this process can be caused by mutations in genes like PRKN and are associated with the development and progression of Parkinson’s Disease (PD). The most used drug in the treatment of PD is levodopa (LD), but it can cause adverse effects, such as dyskinesia. Currently, few studies are searching for biomarkers for an effective use of lLD for this disease, especially regarding mitophagy genetics. Thus, this work investigates the association of 14 variants of the PRKN gene with LD in the treatment of PD. We recruited 70 patients with PD undergoing treatment with LD (39 without dyskinesia and 31 with dyskinesia). Genotyping was based on Sanger sequencing. Our results reinforce that age at onset of symptoms, duration of PD, and treatment and dosage of LD can influence the occurrence of dyskinesia but not the investigated PRKN variants. The perspective presented here of variants of mitophagy-related genes in the context of treatment with LD is still underexplored, although an association has been indicated in previous studies. We suggest that other variants in PRKN or in other mitophagy genes may participate in the development of levodopa-induced dyskinesia in PD treatment. Full article

(This article belongs to the Special Issue Parkinson’s Disease: From Pathophysiology to Novel Therapeutic Approaches)

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12 pages, 9518 KiB

Open AccessArticle

The Effects of Serping1 siRNA in α-Synuclein Regulation in MPTP-Induced Parkinson’s Disease

by Min Hyung Seo and Sujung Yeo

Biomedicines 2023, 11(7), 1952; https://doi.org/10.3390/biomedicines11071952 - 10 Jul 2023

Viewed by 909

Abstract

Our understanding of the gastrointestinal system in the pathophysiology of Parkinson’s disease (PD) has grown considerably over the last two decades. Patients with PD experience notable gastrointestinal symptoms, including constipation. In this study, the effects of knocked-down serping1, associated with the contraction and [...] Read more.

Our understanding of the gastrointestinal system in the pathophysiology of Parkinson’s disease (PD) has grown considerably over the last two decades. Patients with PD experience notable gastrointestinal symptoms, including constipation. In this study, the effects of knocked-down serping1, associated with the contraction and relaxation of smooth muscle and inflammation responses, by applying the serping1 siRNA were investigated in 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine-induced PD mice in an α-syn change aspect. In the result, serping1 expression was knocked down by the treatment of serping1 siRNA, and decreased serping1 induced the decrease α-syn in the colon. Furthermore, the changes in α-syn aggregation were also examined in the brain, and alleviated α-syn aggregation was also observed in an serping1 siRNA treatment group. The results indicated that serping1 siRNA could ease synucleinopathy related to the gastrointestinal system in PD. This study also raises the possibility that serping1 siRNA could alleviate α-syn aggregation in striatum and substantia nigra regions of the brain. Full article

(This article belongs to the Special Issue Parkinson’s Disease: From Pathophysiology to Novel Therapeutic Approaches)

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10 pages, 287 KiB

Open AccessArticle

The Effectiveness and Toxicity of Frameless CyberKnife Based Radiosurgery for Parkinson’s Disease—Phase II Study

by Bartłomiej Goc, Agata Roch-Zniszczoł, Dawid Larysz, Łukasz Zarudzki, Małgorzata Stąpór-Fudzińska, Agnieszka Rożek, Grzegorz Woźniak, Magdalena Boczarska-Jedynak, Leszek Miszczyk and Aleksandra Napieralska

Biomedicines 2023, 11(2), 288; https://doi.org/10.3390/biomedicines11020288 - 20 Jan 2023

Viewed by 1507

Abstract

Frame-based stereotactic radiosurgery (SRS) has an established role in the treatment of tremor in patients with Parkinson’s disease (PD). The low numbers of studies of frameless approaches led to our prospective phase 2 open-label single-arm clinical trial (NCT02406105), which aimed to evaluate the [...] Read more.

Frame-based stereotactic radiosurgery (SRS) has an established role in the treatment of tremor in patients with Parkinson’s disease (PD). The low numbers of studies of frameless approaches led to our prospective phase 2 open-label single-arm clinical trial (NCT02406105), which aimed to evaluate the safety and efficacy of CyberKnife frameless SRS. Twenty-three PD patients were irradiated on the area of the thalamic ventral nuclei complex with gradually increasing doses of 70 to 105 Gy delivered in a single fraction. After SRS, patients were monitored for tremor severity and the toxicity of the treatment. Both subjective improvement and dose-dependent efficacy were analysed using standard statistical tests. The median follow-up was 23 months, and one patient died after COVID-19 infection. Another two patients were lost from follow-up. Hyper-response resulting in vascular toxicity and neurologic complications was observed in two patients irradiated with doses of 95 and 100 Gy, respectively. A reduction in tremor severity was observed in fifteen patients, and six experienced stagnation. A constant response during the whole follow-up was observed in 67% patients. A longer median response time was achieved in patients irradiated with doses equal to or less than 85 Gy. Only two patients declared no improvement after SRS. The efficacy of frameless SRS is high and could improve tremor control in a majority of patients. The complication rate is low, especially when doses below 90 Gy are applied. Frameless SRS could be offered as an alternative for patients ineligible for deep brain stimulation; however, studies regarding optimal dose are required. Full article

(This article belongs to the Special Issue Parkinson’s Disease: From Pathophysiology to Novel Therapeutic Approaches)

15 pages, 1946 KiB

Open AccessArticle

Neuroprotective Effects of Licochalcone D in Oxidative-Stress-Induced Primitive Neural Stem Cells from Parkinson’s Disease Patient-Derived iPSCs

by Minyoung Oh, Juhyeon Nam, Areum Baek, Ji-Hye Seo, Jung-Il Chae, Seo-Young Lee, Sun-Ku Chung, Byoung Chul Park, Sung Goo Park, Janghwan Kim and Young-Joo Jeon

Biomedicines 2023, 11(1), 228; https://doi.org/10.3390/biomedicines11010228 - 16 Jan 2023

Viewed by 2126

Abstract

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases caused by the loss of dopaminergic neurons in the substantia nigra pars compacta. Although the etiology of PD is still unclear, the death of dopaminergic neurons during PD progression was revealed to [...] Read more.

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases caused by the loss of dopaminergic neurons in the substantia nigra pars compacta. Although the etiology of PD is still unclear, the death of dopaminergic neurons during PD progression was revealed to be associated with abnormal aggregation of α-synuclein, elevation of oxidative stress, dysfunction of mitochondrial functions, and increased neuroinflammation. In this study, the effects of Licochalcone D (LCD) on MG132-induced neurotoxicity in primitive neural stem cells (pNSCs) derived from reprogrammed iPSCs were investigated. A cell viability assay showed that LCD had anti-apoptotic properties in MG132-induced oxidative-stressed pNSCs. It was confirmed that apoptosis was reduced in pNSCs treated with LCD through 7-AAD/Annexin Ⅴ staining and cleaved caspase3. These effects of LCD were mediated through an interaction with JunD and through the EGFR/AKT and JNK signaling pathways. These findings suggest that LCD could be a potential antioxidant reagent for preventing disease-related pathological phenotypes of PD. Full article

(This article belongs to the Special Issue Parkinson’s Disease: From Pathophysiology to Novel Therapeutic Approaches)

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17 pages, 3471 KiB

Open AccessArticle

Plasma Metabolic Disturbances in Parkinson’s Disease Patients

by Paulina Gątarek, Joanna Sekulska-Nalewajko, Barbara Bobrowska-Korczaka, Małgorzata Pawełczyk, Karol Jastrzębski, Andrzej Głąbiński and Joanna Kałużna-Czaplińska

Biomedicines 2022, 10(12), 3005; https://doi.org/10.3390/biomedicines10123005 - 22 Nov 2022

Cited by 9 | Viewed by 1948

Abstract

Plasma from patients with Parkinson’s disease (PD) is a valuable source of information indicating altered metabolites associated with the risk or progression of the disease. Neurotoxicity of dopaminergic neurons, which is triggered by aggregation of α-synuclein, is the main pathogenic feature of PD. [...] Read more.

Plasma from patients with Parkinson’s disease (PD) is a valuable source of information indicating altered metabolites associated with the risk or progression of the disease. Neurotoxicity of dopaminergic neurons, which is triggered by aggregation of α-synuclein, is the main pathogenic feature of PD. However, a growing body of scientific reports indicates that metabolic changes may precede and directly contribute to neurodegeneration. Identification and characterization of the abnormal metabolic pattern in patients’ plasma are therefore crucial for the search for potential PD biomarkers. The aims of the present study were (1) to identify metabolic alterations in plasma metabolome in subjects with PD as compared with the controls; (2) to find new potential markers, some correlations among them; (3) to identify metabolic pathways relevant to the pathophysiology of PD. Plasma samples from patients with PD (n = 25) and control group (n = 12) were collected and the gas chromatography-time-of-flight-mass spectrometry GC-TOFMS-based metabolomics approach was used to evaluate the metabolic changes based on the identified 14 metabolites with significantly altered levels using univariate and multivariate statistical analysis. The panel, including 6 metabolites (L-3-methoxytyrosine, aconitic acid, L-methionine, 13-docosenamide, hippuric acid, 9,12-octadecadienoic acid), was identified to discriminate PD from controls with the area under the curve (AUC) of 0.975, with an accuracy of 92%. We also used statistical criteria to identify the significantly altered level of metabolites. The metabolic pathways involved were associated with linoleic acid metabolism, mitochondrial electron transport chain, glycerolipid metabolism, and bile acid biosynthesis. These abnormal metabolic changes in the plasma of patients with PD were mainly related to the amino acid metabolism, TCA cycle metabolism, and mitochondrial function. Full article

(This article belongs to the Special Issue Parkinson’s Disease: From Pathophysiology to Novel Therapeutic Approaches)

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15 pages, 2957 KiB

Open AccessArticle

Neuroprotective Effects of Nicotinamide against MPTP-Induced Parkinson’s Disease in Mice: Impact on Oxidative Stress, Neuroinflammation, Nrf2/HO-1 and TLR4 Signaling Pathways

by Inayat Ur Rehman, Amjad Khan, Riaz Ahmad, Kyonghwan Choe, Hyun Young Park, Hyeon Jin Lee, Abubakar Atiq, Jungsung Park, Jong Ryeal Hahm and Myeong Ok Kim

Biomedicines 2022, 10(11), 2929; https://doi.org/10.3390/biomedicines10112929 - 14 Nov 2022

Cited by 8 | Viewed by 2714

Abstract

Nicotinamide (NAM) is the amide form of niacin and an important precursor of nicotinamide adenine dinucleotide (NAD), which is needed for energy metabolism and cellular functions. Additionally, it has shown neuroprotective properties in several neurodegenerative diseases. Herein, we sought to investigate the potential [...] Read more.

Nicotinamide (NAM) is the amide form of niacin and an important precursor of nicotinamide adenine dinucleotide (NAD), which is needed for energy metabolism and cellular functions. Additionally, it has shown neuroprotective properties in several neurodegenerative diseases. Herein, we sought to investigate the potential protective mechanisms of NAM in an intraperitoneal (i.p) 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson’s disease (PD) mouse model (wild-type mice (C57BL/6N), eight weeks old, average body weight 25–30 g). The study had four groups (n = 10 per group): control, MPTP (30 mg/kg i.p. for 5 days), MPTP treated with NAM (500 mg/kg, i.p for 10 days) and control treated with NAM. Our study showed that MPTP increased the expression of α-synuclein 2.5-fold, decreased tyrosine hydroxylase (TH) 0.5-fold and dopamine transporters (DAT) levels up to 0.5-fold in the striatum and substantia nigra pars compacta (SNpc), and impaired motor function. However, NAM treatment significantly reversed these PD-like pathologies. Furthermore, NAM treatment reduced oxidative stress by increasing the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) between 0.5- and 1.0-fold. Lastly, NAM treatment regulated neuroinflammation by reducing Toll-like receptor 4 (TLR-4), phosphorylated nuclear factor-κB, tumor (p-NFκB), and cyclooxygenase-2 (COX-2) levels by 0.5- to 2-fold in the PD mouse brain. Overall, these findings suggest that NAM exhibits neuroprotective properties and may be an effective therapeutic agent for PD. Full article

(This article belongs to the Special Issue Parkinson’s Disease: From Pathophysiology to Novel Therapeutic Approaches)

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17 pages, 3702 KiB

Open AccessArticle

Natural Compounds Such as Hericium erinaceus and Coriolus versicolor Modulate Neuroinflammation, Oxidative Stress and Lipoxin A4 Expression in Rotenone-Induced Parkinson’s Disease in Mice

by Marika Cordaro, Sergio Modafferi, Ramona D’Amico, Roberta Fusco, Tiziana Genovese, Alessio Filippo Peritore, Enrico Gugliandolo, Rosalia Crupi, Livia Interdonato, Davide Di Paola, Daniela Impellizzeri, Salvatore Cuzzocrea, Vittorio Calabrese, Rosanna Di Paola and Rosalba Siracusa

Biomedicines 2022, 10(10), 2505; https://doi.org/10.3390/biomedicines10102505 - 07 Oct 2022

Cited by 7 | Viewed by 3239

Abstract

Background: A growing body of research suggests that oxidative stress and neuroinflammation are early pathogenic features of neurodegenerative disorders. In recent years, the vitagene system has emerged as a potential target, as it has been shown to have a high neuroprotective power. Therefore, [...] Read more.

Background: A growing body of research suggests that oxidative stress and neuroinflammation are early pathogenic features of neurodegenerative disorders. In recent years, the vitagene system has emerged as a potential target, as it has been shown to have a high neuroprotective power. Therefore, the discovery of molecules capable of activating this system may represent a new therapeutic target to limit the deleterious consequences induced by oxidative stress and neuroinflammation, such as neurodegeneration. Lipoxins are derived from arachidonic acid, and their role in the resolution of systemic inflammation is well established; however, they have become increasingly involved in the regulation of neuroinflammatory and neurodegenerative processes. Our study aimed at activating the NF-E2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) redox system and increasing lipoxin A4 for the modulation of antioxidant stress and neuroinflammation through the action of two fungi in a rotenone-induced Parkinson’s model. Methods: During the experiment, mice received Hericium erinaceus, Coriolus versicolor or a combination of the two (200 mg/kg, orally) concomitantly with rotenone (5 mg/kg, orally) for 28 days. Results: The results obtained highlighted the ability of these two fungi and, in particular, their ability through their association to act on neuroinflammation through the nuclear factor-kB pathway and on oxidative stress through the Nrf2 pathway. This prevented dopaminergic neurons from undergoing apoptosis and prevented the alteration of typical Parkinson’s disease (PD) markers and α-synuclein accumulation. The action of Hericium erinaceus and Coriolus versicolor was also able to limit the motor and non-motor alterations characteristic of PD. Conclusions: Since these two mushrooms are subject to fewer regulations than traditional drugs, they could represent a promising nutraceutical choice for preventing PD. Full article

(This article belongs to the Special Issue Parkinson’s Disease: From Pathophysiology to Novel Therapeutic Approaches)

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Review

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24 pages, 2879 KiB

Open AccessReview

The Impact of microRNAs on Mitochondrial Function and Immunity: Relevance to Parkinson’s Disease

by Beatriz F. S. Guedes, Sandra Morais Cardoso and Ana Raquel Esteves

Biomedicines 2023, 11(5), 1349; https://doi.org/10.3390/biomedicines11051349 - 03 May 2023

Cited by 2 | Viewed by 2159

Abstract

Parkinson’s Disease (PD), the second most common neurodegenerative disorder, is characterised by the severe loss of dopaminergic neurons in the Substantia Nigra pars compacta (SNpc) and by the presence of Lewy bodies. PD is diagnosed upon the onset of motor symptoms, such as [...] Read more.

Parkinson’s Disease (PD), the second most common neurodegenerative disorder, is characterised by the severe loss of dopaminergic neurons in the Substantia Nigra pars compacta (SNpc) and by the presence of Lewy bodies. PD is diagnosed upon the onset of motor symptoms, such as bradykinesia, resting tremor, rigidity, and postural instability. It is currently accepted that motor symptoms are preceded by non-motor features, such as gastrointestinal dysfunction. In fact, it has been proposed that PD might start in the gut and spread to the central nervous system. Growing evidence reports that the gut microbiota, which has been found to be altered in PD patients, influences the function of the central and enteric nervous systems. Altered expression of microRNAs (miRNAs) in PD patients has also been reported, many of which regulate key pathological mechanisms involved in PD pathogenesis, such as mitochondrial dysfunction and immunity. It remains unknown how gut microbiota regulates brain function; however, miRNAs have been highlighted as important players. Remarkably, numerous studies have depicted the ability of miRNAs to modulate and be regulated by the host’s gut microbiota. In this review, we summarize the experimental and clinical studies implicating mitochondrial dysfunction and immunity in PD. Moreover, we gather recent data on miRNA involvement in these two processes. Ultimately, we discuss the reciprocal crosstalk between gut microbiota and miRNAs. Studying the bidirectional interaction of gut microbiome–miRNA might elucidate the aetiology and pathogenesis of gut-first PD, which could lead to the application of miRNAs as potential biomarkers or therapeutical targets for PD. Full article

(This article belongs to the Special Issue Parkinson’s Disease: From Pathophysiology to Novel Therapeutic Approaches)

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