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Novel Concepts, New Perspectives, and Current Therapies for Parkinson's Disease

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (15 January 2024) | Viewed by 18021

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Dr. Malgorzata Zaremba

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1. Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology (CePT), Medical University of Warsaw, 02-927 Warsaw, Poland
2. Laboratory of Experimental Therapies, Military Institute of Hygiene and Epidemiology, Kozielska 4, 01-163 Warsaw, Poland
Interests: Parkinson’s disease; therapy; drug; repurposing; novel compound; neurodegeneration; neuroinflammation
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Dear Colleagues,

Parkinson’s disease (PD), the most common progressive, neurodegenerative movement disorder, is caused by a hypodopaminergic condition in the nigrostriatal system. Cardinal motor symptoms are the main determinant of the quality of life for those with PD, as well as the progression of the disability and possible nursing home placement. As life expectancy increases, the need for novel approaches to treat PD grows urgent. However, while most antiparkinsonian drugs offer symptomatic relief, they do not tackle the underlying etiology of the disease. In addition, there is currently no available therapy that slows down the progression of PD or even prevents its manifestation. The most significant limitations of approved drugs are mostly related to their side effects and lack of long-term efficacy. Therefore, driven by the increasing knowledge of neurodegeneration and neuroinflammation processes, extensive research efforts are underway to identify new strategies to modulate previously undruggable targets or to manage the disease.

The present Special Issue will highlight the state of current pharmacological strategies and explore drug candidates under treatment evaluation, as well as candidates for repurposing for the treatment of PD. Furthermore, this issue will also provide an overview of future studies and novel molecular targets that may be used to combat PD. Hence, for this Special Issue, we are inviting researchers to contribute original articles and reviews on these topics. Contributions from all research areas, including disease modeling, drug studies, and therapeutic interventions, are welcome.

I look forward to receiving your contributions.

Dr. Malgorzata Zaremba
Guest Editor

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Keywords

Parkinson’s disease
therapy
drug
repurposing
novel compound
neurodegeneration
neuroinflammation

Related Special Issue

Novel Concepts, New Perspectives, and Current Therapies for Parkinson’s Disease: 2nd Edition in International Journal of Molecular Sciences

Published Papers (9 papers)

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Research

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17 pages, 6671 KiB

Open AccessArticle

Impact of Serotonergic 5HT_1A and 5HT_2A Receptor Activation on the Respiratory Response to Hypercapnia in a Rat Model of Parkinson’s Disease

by Kryspin Andrzejewski, Magdalena E. Orłowska, Małgorzata Zaremba, Ilona Joniec-Maciejak and Katarzyna Kaczyńska

Int. J. Mol. Sci. 2024, 25(8), 4403; https://doi.org/10.3390/ijms25084403 - 17 Apr 2024

Viewed by 498

Abstract

In Parkinson’s disease (PD), along with typical motor dysfunction, abnormal breathing is present; the cause of which is not well understood. The study aimed to analyze the effects of stimulation of the serotonergic system with 5-HT_1A and 5-HT_2A agonists in a model of PD induced by injection of 6-hydroxydopamine (6-OHDA). To model PD, bilateral injection of 6-OHDA into both striata was performed in male Wistar rats. Respiratory disturbances in response to 7% hypercapnia (CO₂ in O₂) in the plethysmographic chamber before and after stimulation of the serotonergic system and the incidence of apnea were studied in awake rats 5 weeks after 6-OHDA or vehicle injection. Administration of 6-OHDA reduced the concentration of serotonin (5-HT), dopamine (DA) and norepinephrine (NA) in the striatum and the level of 5-HT in the brainstem of treated rats, which have been associated with decreased basal ventilation, impaired respiratory response to 7% CO₂ and increased incidence of apnea compared to Sham-operated rats. Intraperitoneal (i.p.) injection of the 5-HT_1AR agonist 8-OH-DPAT and 5-HT_2AR agonist NBOH-2C-CN increased breathing during normocapnia and hypercapnia in both groups of rats. However, it restored reactivity to hypercapnia in 6-OHDA group to the level present in Sham rats. Another 5-HT_2AR agonist TCB-2 was only effective in increasing normocapnic ventilation in 6-OHDA rats. Both the serotonergic agonists 8-OH-DPAT and NBOH-2C-CN had stronger stimulatory effects on respiration in PD rats, compensating for deficits in basal ventilation and hypercapnic respiration. We conclude that serotonergic stimulation may have a positive effect on respiratory impairments that occur in PD. Full article

(This article belongs to the Special Issue Novel Concepts, New Perspectives, and Current Therapies for Parkinson's Disease)

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17 pages, 2047 KiB

Open AccessArticle

Molecular Behavior of α-Synuclein Is Associated with Membrane Transport, Lipid Metabolism, and Ubiquitin–Proteasome Pathways in Lewy Body Disease

by Tomoya Kon, Seojin Lee, Ivan Martinez-Valbuena, Koji Yoshida, Satoshi Tanikawa, Anthony E. Lang and Gabor G. Kovacs

Int. J. Mol. Sci. 2024, 25(5), 2676; https://doi.org/10.3390/ijms25052676 - 26 Feb 2024

Viewed by 936

Abstract

Lewy body diseases (LBDs) feature α-synuclein (α-syn)-containing Lewy bodies, with misfolded α-syn potentially propagating as seeds. Using a seeding amplification assay, we previously reported distinct α-syn seeding in LBD cases based on the area under seeding curves. This study revealed that LBD cases showing different α-syn seeding kinetics have distinct proteomics profiles, emphasizing disruptions in mitochondria and lipid metabolism in high-seeder cases. Though the mechanisms underlying LBD development are intricate, the factors influencing α-syn seeding activity remain elusive. To address this and complement our previous findings, we conducted targeted transcriptome analyses in the substantia nigra using the nanoString nCounter assay together with histopathological evaluations in high (n = 4) and low (n = 3) nigral α-syn seeders. Neuropathological findings (particularly the substantia nigra) were consistent between these groups and were characterized by neocortical LBD associated with Alzheimer’s disease neuropathologic change. Among the 1811 genes assessed, we identified the top 20 upregulated and downregulated genes and pathways in α-syn high seeders compared with low seeders. Notably, alterations were observed in genes and pathways related to transmembrane transporters, lipid metabolism, and the ubiquitin–proteasome system in the high α-syn seeders. In conclusion, our findings suggest that the molecular behavior of α-syn is the driving force in the neurodegenerative process affecting the substantia nigra through these identified pathways. These insights highlight their potential as therapeutic targets for attenuating LBD progression. Full article

(This article belongs to the Special Issue Novel Concepts, New Perspectives, and Current Therapies for Parkinson's Disease)

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16 pages, 3551 KiB

Open AccessArticle

A Novel NOX Inhibitor Alleviates Parkinson’s Disease Pathology in PFF-Injected Mice

by Kwadwo Ofori, Anurupa Ghosh, Dinesh Kumar Verma, Darice Wheeler, Gabriela Cabrera, Jong-Bok Seo and Yong-Hwan Kim

Int. J. Mol. Sci. 2023, 24(18), 14278; https://doi.org/10.3390/ijms241814278 - 19 Sep 2023

Viewed by 1074

Abstract

Oxidative stress-mediated damage is often a downstream result of Parkinson’s disease (PD), which is marked by sharp decline in dopaminergic neurons within the nigrostriatal regions of the brain, accounting for the symptomatic motor deficits in patients. Regulating the level of oxidative stress may present a beneficial approach in preventing PD pathology. Here, we assessed the efficacy of a nicotinamide adenine phosphate (NADPH) oxidase (NOX) inhibitor, an exogenous reactive oxygen species (ROS) regulator synthesized by Aptabio therapeutics with the specificity to NOX-1, 2 and 4. Utilizing N27 rat dopaminergic cells and C57Bl/6 mice, we confirmed that the exposures of alpha-synuclein preformed fibrils (PFF) induced protein aggregation, a hallmark in PD pathology. In vitro assessment of the novel compound revealed an increase in cell viability and decreases in cytotoxicity, ROS, and protein aggregation (Thioflavin-T stain) against PFF exposure at the optimal concentration of 10 nM. Concomitantly, the oral treatment alleviated motor-deficits in behavioral tests, such as hindlimb clasping, rotarod, pole, nesting and grooming test, via reducing protein aggregation, based on rescued dopaminergic neuronal loss. The suppression of NOX-1, 2 and 4 within the striatum and ventral midbrain regions including Substantia Nigra compacta (SNc) contributed to neuroprotective/recovery effects, making it a potential therapeutic option for PD. Full article

(This article belongs to the Special Issue Novel Concepts, New Perspectives, and Current Therapies for Parkinson's Disease)

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14 pages, 3572 KiB

Open AccessArticle

Dihydroisotanshinone I and BMAL-SIRT1 Pathway in an In Vitro 6-OHDA-Induced Model of Parkinson’s Disease

by Hui-Chen Su, Yuan-Ting Sun, Ming-Yu Yang, Ching-Yuan Wu and Cheng-Ming Hsu

Int. J. Mol. Sci. 2023, 24(13), 11088; https://doi.org/10.3390/ijms241311088 - 4 Jul 2023

Cited by 1 | Viewed by 1489

Abstract

Danshen has been widely used for the treatment of central nervous system diseases. We investigated the effect of dihydroisotanshinone I (DT), a compound extracted from Danshen, as well as the corresponding mechanisms in an in vitro-based 6-OHDA-induced Parkinson’s disease (PD) model. SH-SY5Y human neuroblastoma cell lines were pretreated with 6-hydroxydopamine (6-OHDA) and challenged with DT. Subsequently, the cell viability and levels of reactive oxygen species (ROS) and caspase-3 were analyzed. The effect of DT on the 6-OHDA-treated SH-SY5Y cells and the expression of the core circadian clock genes were measured using a real-time quantitative polymerase chain reaction. Our results indicated that DT attenuated the 6-OHDA-induced cell death in the SH-SY5Y cells and suppressed ROS and caspase-3. Moreover, DT reversed both the RNA and protein levels of BMAL1 and SIRT1 in the 6-OHDA-treated SH-SY5Y cells. Additionally, the SIRT1 inhibitor attenuated the effect of DT on BMAL1 and reduced the cell viability. The DT and SIRT1 activators activated SIRT1 and BMAL1, and then reduced the death of the SH-SY5Y cells damaged by 6-OHDA. SIRT1 silencing was enhanced by DT and resulted in a BMAL1 downregulation and a reduction in cell viability. In conclusion, our investigation suggested that DT reduces cell apoptosis, including an antioxidative effect due to a reduction in ROS, and regulates the circadian genes by enhancing SIRT1 and suppressing BMAL1. DT may possess novel therapeutic potential for PD in the future, but further in vivo studies are still needed. Full article

(This article belongs to the Special Issue Novel Concepts, New Perspectives, and Current Therapies for Parkinson's Disease)

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16 pages, 3532 KiB

Open AccessArticle

Low-Field Magnetic Stimulation Alleviates MPTP-Induced Alterations in Motor Function and Dopaminergic Neurons in Male Mice

by Sathiya Sekar, Yanbo Zhang, Hajar Miranzadeh Mahabadi, Benson Buettner and Changiz Taghibiglou

Int. J. Mol. Sci. 2023, 24(12), 10328; https://doi.org/10.3390/ijms241210328 - 19 Jun 2023

Cited by 1 | Viewed by 1880

Abstract

Recent studies show that repetitive transcranial magnetic stimulation (rTMS) improves cognitive and motor functions in patients with Parkinson’s Disease (PD). Gamma rhythm low-field magnetic stimulation (LFMS) is a new non-invasive rTMS technique that generates diffused and low-intensity magnetic stimulation to the deep cortical and subcortical areas. To investigate the potential therapeutic effects of LFMS in PD, we subjected an experimental mouse model to LFMS (as an early treatment). We examined the LFMS effect on motor functions as well as neuronal and glial activities in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated male C57BL/6J mice. Mice received MPTP injection (30 mg/kg, i.p., once daily for 5 days) followed by LFMS treatment, 20 min each day for 7 days. LFMS treatment improved motor functions compared with the sham-treated MPTP mice. Further, LFMS significantly improved tyrosine hydroxylase (TH) and decreased glial fibrillary acidic protein (GFAP) levels in substantia nigra pars compacta (SNpc) and non-significantly in striatal (ST) regions. LFMS treatment improved neuronal nuclei (NeuN) levels in SNpc. Our findings suggest that early LFMS treatment improves neuronal survival and, in turn, motor functions in MPTP-treated mice. Further investigation is required to clearly define the molecular mechanisms by which LFMS improves motor and cognitive function in PD patients. Full article

(This article belongs to the Special Issue Novel Concepts, New Perspectives, and Current Therapies for Parkinson's Disease)

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12 pages, 3391 KiB

Open AccessArticle

Cathepsin B p.Gly284Val Variant in Parkinson’s Disease Pathogenesis

by Lukasz M. Milanowski, Xu Hou, Jenny M. Bredenberg, Fabienne C. Fiesel, Liam T. Cocker, Alexandra I. Soto-Beasley, Ronald L. Walton, Audrey J. Strongosky, Ayman H. Faroqi, Maria Barcikowska, Magdalena Boczarska-Jedynak, Jaroslaw Dulski, Lyuda Fedoryshyn, Piotr Janik, Anna Potulska-Chromik, Katherine Karpinsky, Anna Krygowska-Wajs, Tim Lynch, Diana A. Olszewska, Grzegorz Opala, Aleksander Pulyk, Irena Rektorova, Yanosh Sanotsky, Joanna Siuda, Mariusz Widlak, Jaroslaw Slawek, Monika Rudzinska-Bar, Ryan Uitti, Monika Figura, Stanislaw Szlufik, Sylwia Rzonca-Niewczas, Elzbieta Podgorska, Pamela J. McLean, Dariusz Koziorowski, Owen A. Ross, Dorota Hoffman-Zacharska, Wolfdieter Springer and Zbigniew K. Wszolek Show full author list Hide full author list

Int. J. Mol. Sci. 2022, 23(13), 7086; https://doi.org/10.3390/ijms23137086 - 25 Jun 2022

Cited by 6 | Viewed by 2519

Abstract

Parkinson’s disease (PD) is generally considered a sporadic disorder, but a strong genetic background is often found. The aim of this study was to identify the underlying genetic cause of PD in two affected siblings and to subsequently assess the role of mutations in Cathepsin B (CTSB) in susceptibility to PD. A typical PD family was identified and whole-exome sequencing was performed in two affected siblings. Variants of interest were validated using Sanger sequencing. CTSB p.Gly284Val was genotyped in 2077 PD patients and 615 unrelated healthy controls from the Czech Republic, Ireland, Poland, Ukraine, and the USA. The gene burden analysis was conducted for the CTSB gene in an additional 769 PD probands from Mayo Clinic Florida familial PD cohort. CTSB expression and activity in patient-derived fibroblasts and controls were evaluated by qRT-PCR, western blot, immunocytochemistry, and enzymatic assay. The CTSB p.Gly284Val candidate variant was only identified in affected family members. Functional analysis of CTSB patient-derived fibroblasts under basal conditions did not reveal overt changes in endogenous expression, subcellular localization, or enzymatic activity in the heterozygous carrier of the CTSB variant. The identification of the CTSB p.Gly284Val may support the hypothesis that the CTSB locus harbors variants with differing penetrance that can determine the disease risk. Full article

(This article belongs to the Special Issue Novel Concepts, New Perspectives, and Current Therapies for Parkinson's Disease)

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Review

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24 pages, 874 KiB

Open AccessReview

The Potentiality of Natural Products and Herbal Medicine as Novel Medications for Parkinson’s Disease: A Promising Therapeutic Approach

by Yu-Jin So, Jae-Ung Lee, Ga-Seung Yang, Gabsik Yang, Sung-Wook Kim, Jun-Ho Lee and Jong-Uk Kim

Int. J. Mol. Sci. 2024, 25(2), 1071; https://doi.org/10.3390/ijms25021071 - 15 Jan 2024

Cited by 2 | Viewed by 1785

Abstract

As the global population ages, the prevalence of Parkinson’s disease (PD) is steadily on the rise. PD demonstrates chronic and progressive characteristics, and many cases can transition into dementia. This increases societal and economic burdens, emphasizing the need to find effective treatments. Among the widely recognized causes of PD is the abnormal accumulation of proteins, and autophagy dysfunction accelerates this accumulation. The resultant Lewy bodies are also commonly found in Alzheimer’s disease patients, suggesting an increased potential for the onset of dementia. Additionally, the production of free radicals due to mitochondrial dysfunction contributes to neuronal damage and degeneration. The activation of astrocytes and the M1 phenotype of microglia promote damage to dopamine neurons. The drugs currently used for PD only delay the clinical progression and exacerbation of the disease without targeting its root cause, and come with various side effects. Thus, there is a demand for treatments with fewer side effects, with much potential offered by natural products. In this study, we reviewed a total of 14 articles related to herbal medicines and natural products and investigated their relevance to possible PD treatment. The results showed that the reviewed herbal medicines and natural products are effective against lysosomal disorder, mitochondrial dysfunction, and inflammation, key mechanisms underlying PD. Therefore, natural products and herbal medicines can reduce neurotoxicity and might improve both motor and non-motor symptoms associated with PD. Furthermore, these products, with their multi-target effects, enhance bioavailability, inhibit antibiotic resistance, and might additionally eliminate side effects, making them good alternative therapies for PD treatment. Full article

(This article belongs to the Special Issue Novel Concepts, New Perspectives, and Current Therapies for Parkinson's Disease)

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21 pages, 1889 KiB

Open AccessReview

The Potential Roles of Extracellular Vesicles as Biomarkers for Parkinson’s Disease: A Systematic Review

by Jessica Valencia, Marta Ferreira, J. Francisco Merino-Torres, Antonio Marcilla and Jose M. Soriano

Int. J. Mol. Sci. 2022, 23(19), 11508; https://doi.org/10.3390/ijms231911508 - 29 Sep 2022

Cited by 9 | Viewed by 2871

Abstract

Parkinson’s disease (PD) is a slowly progressive neurodegenerative disorder, characterized by the misfolding and aggregation of α-synuclein (α-syn) into Lewy bodies and the degeneration of dopaminergic neurons in the substantia nigra pars compacta. The urge for an early diagnosis biomarker comes from the fact that clinical manifestations of PD are estimated to appear once the substantia nigra has deteriorated and there has been a reduction of the dopamine levels from the striatum. Nowadays, extracellular vesicles (EVs) play an important role in the pathogenesis of neuro-degenerative diseases as PD. A systematic review dated August 2022 was carried out with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses with the aim to analyze the potential role of EVs as biomarkers for PD. From a total of 610 articles retrieved, 29 were eligible. This review discusses the role of EVs biochemistry and their cargo proteins, such as α-syn and DJ-1 among others, detected by a proteomic analysis as well as miRNAs and lncRNAs, as potential biomarkers that can be used to create standardized protocols for early PD diagnosis as well as to evaluate disease severity and progression. Full article

(This article belongs to the Special Issue Novel Concepts, New Perspectives, and Current Therapies for Parkinson's Disease)

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Other

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11 pages, 1165 KiB

Open AccessPerspective

Parkinson’s Disease Etiology: Insights and Associations with Phosphate Toxicity

by Ronald B. Brown

Int. J. Mol. Sci. 2022, 23(15), 8060; https://doi.org/10.3390/ijms23158060 - 22 Jul 2022

Cited by 4 | Viewed by 3358

Abstract

The present paper investigated the association of Parkinson’s disease etiology with phosphate toxicity, a pathophysiological condition in which dysregulated phosphate metabolism causes excessive inorganic phosphate sequestration in body tissue that damages organ systems. Excessive phosphate is proposed to reduce Complex I function of the mitochondrial electron transport chain in Parkinson’s disease and is linked to opening of the mitochondrial permeability transition pore, resulting in increased reactive oxygen species, inflammation, DNA damage, mitochondrial membrane depolarization, and ATP depletion causing cell death. Parkinson’s disease is associated with α-synuclein and Lewy body dementia, a secondary tauopathy related to hyperphosphorylation of tau protein, and tauopathy is among several pathophysiological pathways shared between Parkinson’s disease and diabetes. Excessive phosphate is also associated with ectopic calcification, bone mineral disorders, and low levels of serum vitamin D in patients with Parkinson’s disease. Sarcopenia and cancer in Parkinson’s disease patients are also associated with phosphate toxicity. Additionally, Parkinson’s disease benefits are related to low dietary phosphate intake. More studies are needed to investigate the potential mediating role of phosphate toxicity in the etiology of Parkinson’s disease. Full article

(This article belongs to the Special Issue Novel Concepts, New Perspectives, and Current Therapies for Parkinson's Disease)

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