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Biomolecules
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Potential Molecular Targets for Disease—Modifying Therapeutic Strategies in Parkinson’s Disease
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Potential Molecular Targets for Disease—Modifying Therapeutic Strategies in Parkinson’s Disease

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Cellular Biochemistry".

Deadline for manuscript submissions: closed (31 July 2020) | Viewed by 48559

Special Issue Editor

Dr. Jordi Bové

E-Mail Website
Guest Editor
Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute (VHIR)-Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), 08035 Barcelona, Spain
Interests: Parkinson’s disease; mechanisms of neuronal death; alpha-synuclein; immune response; mitochondrial mediated cell death; lysosomal impairment; transcription factor EB; neuroprotective strategies

Special Issue Information

Dear Colleagues,

A century ago, Konstantin Tretiakoff reported that substantia nigra pars compacta was the main anatomical substrate of Parkinson’s disease (PD). So far, scientists in the field have not been able to elucidate the primary cause of neuronal cell death in this pathological condition. Several neuron-autonomous and non-neuron-autonomous mechanisms have been suggested to contribute to neurodegeneration. Mitochondrial dysfunction, oxidative and endoplasmic reticulum stress, impairment of the degradation pathways, protein aggregation, and programmed cell death are some of the neuron-autonomous mechanisms that have been proposed. Among the non-neuron-autonomous mechanisms, neuroinflammation has been the most studied. Even though several strategies targeting some of those mechanisms are neuroprotective in PD animal models, none of the clinical trials carried out to date to halt the progression of the disease have been satisfactory. Therefore, we need to try different approaches if we want different results and to cure this disabling disease.

The goal of this Special Issue is precisely to inspire all of us with new approaches and perspectives regarding potential therapeutic targets and the mechanisms of neuronal cell death in PD. We encourage researchers in the field to contribute review articles on neuron-autonomous and non-neuron-autonomous mechanisms/targets that help us to separate the wheat from the chaff, regardless of whether their hypotheses are mainstream. We are also open to original papers that assess new targets or old targets with new perspectives or methodologies.

Dr. Jordi Bové
Guest Editor

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Keywords

  • Parkinson’s disease
  • neuronal death mechanisms
  • targets for neuroprotection
  • genetic risk factors

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Published Papers (7 papers)

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Research

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15 pages, 1091 KiB  
Communication
Prolyl Endopeptidase-Like Facilitates the α-Synuclein Aggregation Seeding, and This Effect Is Reverted by Serine Peptidase Inhibitor PMSF
by Gabriel S. Santos, William Y. Oyadomari, Elizangela A. Carvalho, Ricardo S. Torquato and Vitor Oliveira
Biomolecules 2020, 10(6), 962; https://doi.org/10.3390/biom10060962 - 25 Jun 2020
Cited by 4 | Viewed by 3163
Abstract
The aggregation of α-synuclein (α-Syn) is a characteristic of Parkinson’s disease (PD). α-Syn oligomerization/aggregation is accelerated by the serine peptidase, prolyl oligopeptidase (POP). Factors that affect POP conformation, including most of its inhibitors and an impairing mutation in its active site, influence the [...] Read more.
The aggregation of α-synuclein (α-Syn) is a characteristic of Parkinson’s disease (PD). α-Syn oligomerization/aggregation is accelerated by the serine peptidase, prolyl oligopeptidase (POP). Factors that affect POP conformation, including most of its inhibitors and an impairing mutation in its active site, influence the acceleration of α-Syn aggregation resulting from the interaction of these proteins. It is noteworthy, however, that α-Syn is not cleaved by POP. Prolyl endopeptidase-like (PREPL) protein is structurally related to the serine peptidases belonging to the POP family. Based on the α-Syn–POP studies and knowing that PREPL may contribute to the regulation of synaptic vesicle exocytosis, when this protein can encounter α-Syn, we investigated the α-Syn–PREPL interaction. The binding of these two human proteins was observed with an apparent affinity constant of about 5.7 μM and, as in the α-Syn assays with POP, the presence of PREPL accelerated the oligomerization/aggregation events, with no α-Syn cleavage. Furthermore, despite this lack of hydrolytic cleavage, the serine peptidase active site inhibitor phenylmethylsulfonyl fluoride (PMSF) abolished the enhancement of the α-Syn aggregation by PREPL. Therefore, given the attention to POP inhibitors as potential drugs to treat synucleinopathies, the present data point to PREPL as another potential target to be explored for this purpose. Full article
(This article belongs to the Special Issue Potential Molecular Targets for Disease—Modifying Therapeutic Strategies in Parkinson’s Disease)
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Review

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35 pages, 1893 KiB  
Review
Extracellular Vesicles as Nanotherapeutics for Parkinson’s Disease
by Loredana Leggio, Greta Paternò, Silvia Vivarelli, Francesca L’Episcopo, Cataldo Tirolo, Gabriele Raciti, Fabrizio Pappalardo, Carmela Giachino, Salvatore Caniglia, Maria Francesca Serapide, Bianca Marchetti and Nunzio Iraci
Biomolecules 2020, 10(9), 1327; https://doi.org/10.3390/biom10091327 - 16 Sep 2020
Cited by 23 | Viewed by 6589
Abstract
Extracellular vesicles (EVs) are naturally occurring membranous structures secreted by normal and diseased cells, and carrying a wide range of bioactive molecules. In the central nervous system (CNS), EVs are important in both homeostasis and pathology. Through receptor–ligand interactions, direct fusion, or endocytosis, [...] Read more.
Extracellular vesicles (EVs) are naturally occurring membranous structures secreted by normal and diseased cells, and carrying a wide range of bioactive molecules. In the central nervous system (CNS), EVs are important in both homeostasis and pathology. Through receptor–ligand interactions, direct fusion, or endocytosis, EVs interact with their target cells. Accumulating evidence indicates that EVs play crucial roles in the pathogenesis of many neurodegenerative disorders (NDs), including Parkinson′s disease (PD). PD is the second most common ND, characterized by the progressive loss of dopaminergic (DAergic) neurons within the Substantia Nigra pars compacta (SNpc). In PD, EVs are secreted by both neurons and glial cells, with either beneficial or detrimental effects, via a complex program of cell-to-cell communication. The functions of EVs in PD range from their etiopathogenetic relevance to their use as diagnostic tools and innovative carriers of therapeutics. Because they can cross the blood–brain barrier, EVs can be engineered to deliver bioactive molecules (e.g., small interfering RNAs, catalase) within the CNS. This review summarizes the latest findings regarding the role played by EVs in PD etiology, diagnosis, prognosis, and therapy, with a particular focus on their use as novel PD nanotherapeutics. Full article
(This article belongs to the Special Issue Potential Molecular Targets for Disease—Modifying Therapeutic Strategies in Parkinson’s Disease)
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32 pages, 1243 KiB  
Review
The Future of Targeted Gene-Based Treatment Strategies and Biomarkers in Parkinson’s Disease
by Alexia Polissidis, Lilian Petropoulou-Vathi, Modestos Nakos-Bimpos and Hardy J. Rideout
Biomolecules 2020, 10(6), 912; https://doi.org/10.3390/biom10060912 - 16 Jun 2020
Cited by 26 | Viewed by 9299
Abstract
Biomarkers and disease-modifying therapies are both urgent unmet medical needs in the treatment of Parkinson’s disease (PD) and must be developed concurrently because of their interdependent relationship: biomarkers for the early detection of disease (i.e., prior to overt neurodegeneration) are necessary in order [...] Read more.
Biomarkers and disease-modifying therapies are both urgent unmet medical needs in the treatment of Parkinson’s disease (PD) and must be developed concurrently because of their interdependent relationship: biomarkers for the early detection of disease (i.e., prior to overt neurodegeneration) are necessary in order for patients to receive maximal therapeutic benefit and vice versa; disease-modifying therapies must become available for patients whose potential for disease diagnosis and prognosis can be predicted with biomarkers. This review provides an overview of the milestones achieved to date in the therapeutic strategy development of disease-modifying therapies and biomarkers for PD, with a focus on the most common and advanced genetically linked targets alpha-synuclein (SNCA), leucine-rich repeat kinase-2 (LRRK2) and glucocerebrosidase (GBA1). Furthermore, we discuss the convergence of the different pathways and the importance of patient stratification and how these advances may apply more broadly to idiopathic PD. The heterogeneity of PD poses a challenge for therapeutic and biomarker development, however, the one gene- one target approach has brought us closer than ever before to an unprecedented number of clinical trials and biomarker advancements. Full article
(This article belongs to the Special Issue Potential Molecular Targets for Disease—Modifying Therapeutic Strategies in Parkinson’s Disease)
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22 pages, 2768 KiB  
Review
Soluble Epoxide Hydrolase Inhibition to Face Neuroinflammation in Parkinson’s Disease: A New Therapeutic Strategy
by Mercè Pallàs, Santiago Vázquez, Coral Sanfeliu, Carles Galdeano and Christian Griñán-Ferré
Biomolecules 2020, 10(5), 703; https://doi.org/10.3390/biom10050703 - 1 May 2020
Cited by 23 | Viewed by 4840
Abstract
Neuroinflammation is a crucial process associated with the pathogenesis of neurodegenerative diseases, including Parkinson’s disease (PD). Several pieces of evidence suggest an active role of lipid mediators, especially epoxy-fatty acids (EpFAs), in the genesis and control of neuroinflammation; 14,15-epoxyeicosatrienoic acid (14,15-EET) is one [...] Read more.
Neuroinflammation is a crucial process associated with the pathogenesis of neurodegenerative diseases, including Parkinson’s disease (PD). Several pieces of evidence suggest an active role of lipid mediators, especially epoxy-fatty acids (EpFAs), in the genesis and control of neuroinflammation; 14,15-epoxyeicosatrienoic acid (14,15-EET) is one of the most commonly studied EpFAs, with anti-inflammatory properties. Soluble epoxide hydrolase (sEH) is implicated in the hydrolysis of 14,15-EET to its corresponding diol, which lacks anti-inflammatory properties. Preventing EET degradation thus increases its concentration in the brain through sEH inhibition, which represents a novel pharmacological approach to foster the reduction of neuroinflammation and by end neurodegeneration. Recently, it has been shown that sEH levels increase in brains of PD patients. Moreover, the pharmacological inhibition of the hydrolase domain of the enzyme or the use of sEH knockout mice reduced the deleterious effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration. This paper overviews the knowledge of sEH and EETs in PD and the importance of blocking its hydrolytic activity, degrading EETs in PD physiopathology. We focus on imperative neuroinflammation participation in the neurodegenerative process in PD and the putative therapeutic role for sEH inhibitors. In this review, we also describe highlights in the general knowledge of the role of sEH in the central nervous system (CNS) and its participation in neurodegeneration. We conclude that sEH is one of the most promising therapeutic strategies for PD and other neurodegenerative diseases with chronic inflammation process, providing new insights into the crucial role of sEH in PD pathophysiology as well as a singular opportunity for drug development. Full article
(This article belongs to the Special Issue Potential Molecular Targets for Disease—Modifying Therapeutic Strategies in Parkinson’s Disease)
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54 pages, 739 KiB  
Review
Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts
by Margaux Teil, Marie-Laure Arotcarena, Emilie Faggiani, Florent Laferriere, Erwan Bezard and Benjamin Dehay
Biomolecules 2020, 10(3), 391; https://doi.org/10.3390/biom10030391 - 3 Mar 2020
Cited by 45 | Viewed by 7330
Abstract
Parkinson’s Disease (PD) is characterized both by the loss of dopaminergic neurons in the substantia nigra and the presence of cytoplasmic inclusions called Lewy Bodies. These Lewy Bodies contain the aggregated α-synuclein (α-syn) protein, which has been shown to be able to propagate [...] Read more.
Parkinson’s Disease (PD) is characterized both by the loss of dopaminergic neurons in the substantia nigra and the presence of cytoplasmic inclusions called Lewy Bodies. These Lewy Bodies contain the aggregated α-synuclein (α-syn) protein, which has been shown to be able to propagate from cell to cell and throughout different regions in the brain. Due to its central role in the pathology and the lack of a curative treatment for PD, an increasing number of studies have aimed at targeting this protein for therapeutics. Here, we reviewed and discussed the many different approaches that have been studied to inhibit α-syn accumulation via direct and indirect targeting. These analyses have led to the generation of multiple clinical trials that are either completed or currently active. These clinical trials and the current preclinical studies must still face obstacles ahead, but give hope of finding a therapy for PD with time. Full article
(This article belongs to the Special Issue Potential Molecular Targets for Disease—Modifying Therapeutic Strategies in Parkinson’s Disease)
17 pages, 1031 KiB  
Review
The Challenge of Disease-Modifying Therapies in Parkinson’s Disease: Role of CSF Biomarkers
by Federico Paolini Paoletti, Lorenzo Gaetani and Lucilla Parnetti
Biomolecules 2020, 10(2), 335; https://doi.org/10.3390/biom10020335 - 19 Feb 2020
Cited by 26 | Viewed by 6094
Abstract
The development of disease modifying strategies in Parkinson’s disease (PD) largely depends on the ability to identify suitable populations after accurate diagnostic work-up. Therefore, patient molecular profiling and disease subtyping are mandatory. Thus far, in clinical trials, PD has been considered to be [...] Read more.
The development of disease modifying strategies in Parkinson’s disease (PD) largely depends on the ability to identify suitable populations after accurate diagnostic work-up. Therefore, patient molecular profiling and disease subtyping are mandatory. Thus far, in clinical trials, PD has been considered to be a “single entity”. Conversely, in front of the common feature of nigro-striatal degeneration, PD is pathogenically heterogeneous with a series of several biological and molecular pathways that differently contribute to clinical development and progression. Currently available diagnostic criteria for PD mainly rely on clinical features and imaging biomarkers, thus missing to identify the contribution of pathophysiological pathways, also failing to catch abnormalities occurring in the early stages of disease. Cerebrospinal fluid (CSF) is a promising source of biomarkers, with the high potential for reflecting early changes occurring in PD brain. In this review, we provide an overview on CSF biomarkers in PD, discussing their association with different molecular pathways involved either in pathophysiology or progression in detail. Their potential application in the field of disease modifying treatments is also discussed. Full article
(This article belongs to the Special Issue Potential Molecular Targets for Disease—Modifying Therapeutic Strategies in Parkinson’s Disease)
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14 pages, 1400 KiB  
Review
Copper Ions and Parkinson’s Disease: Why Is Homeostasis So Relevant?
by Marco Bisaglia and Luigi Bubacco
Biomolecules 2020, 10(2), 195; https://doi.org/10.3390/biom10020195 - 29 Jan 2020
Cited by 138 | Viewed by 10263
Abstract
The involvement of copper in numerous physiological processes makes this metal ion essential for human life. Alterations in copper homeostasis might have deleterious consequences, and several neurodegenerative disorders, including Parkinson’s disease (PD), have been associated with impaired copper levels. In the present review, [...] Read more.
The involvement of copper in numerous physiological processes makes this metal ion essential for human life. Alterations in copper homeostasis might have deleterious consequences, and several neurodegenerative disorders, including Parkinson’s disease (PD), have been associated with impaired copper levels. In the present review, we describe the molecular mechanisms through which copper can exert its toxicity, by considering how it can interfere with other cellular processes known to play a role in PD, such as dopamine metabolism, oxidative stress, and α-synuclein aggregation. The recent experimental evidence that associates copper deficiency and the formation of superoxide dismutase 1 (SOD1) aggregates with the progression of PD is also discussed together with its therapeutic implication. Overall, the recent discoveries described in this review show how either copper deficiency or excessive levels can promote detrimental effects, highlighting the importance of preserving copper homeostasis and opening unexplored therapeutic avenues in the definition of novel disease-modifying drugs. Full article
(This article belongs to the Special Issue Potential Molecular Targets for Disease—Modifying Therapeutic Strategies in Parkinson’s Disease)
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