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The Molecular and Cellular Basis for Parkinson's Disease

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Nervous System".

Deadline for manuscript submissions: closed (31 March 2019) | Viewed by 95087

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Special Issue Editor

Prof. Dr. Thomas Müller

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Guest Editor

Department of Neurology, St. Joseph Hospital Berlin-Weissensee, Berlin, Germany
Interests: neurology; psychiatry; pain; Parkinson's disease; multiple sclerosis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The focus on dopamine-sensitive motor symptoms, in association with improvement of motor complications in the heterogeneous disease entity Parkinson's disease, leads to a certain standstill in research.

This Special Issue aims to provide new concepts and new ideas on the pathogenesis, genetics, and clinical maintenance of Parkinson's disease and related disorders. Not only new experimental findings, but also clinical outcomes, case series, and research on alternative, non-pharmacological therapies, will be considered.

The objective is to bridge the currently-increasing gap between experimental and clinical research on Parkinson's disease and related disorders.

Prof. Thomas Müller
Guest Editor

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Keywords

Bridge between experimental and clinical research in PD
Disease modification in PD
Mechanisms of chronic neurodegeneration
Pros and cons of animal models in PD
Microbiome research in PD
Alternative therapies in PD
Non-pharmacological therapies in PD

Published Papers (12 papers)

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Research

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23 pages, 6196 KiB

Open AccessArticle

Reappraisal of Human HOG and MO3.13 Cell Lines as a Model to Study Oligodendrocyte Functioning

by Kim M. A. De Kleijn, Wieteke A. Zuure, Jolien Peijnenborg, Josje M. Heuvelmans and Gerard J. M. Martens

Cells 2019, 8(9), 1096; https://doi.org/10.3390/cells8091096 - 17 Sep 2019

Cited by 18 | Viewed by 7074

Abstract

Myelination of neuronal axons is essential for proper brain functioning and requires mature myelinating oligodendrocytes (myOLs). The human OL cell lines HOG and MO3.13 have been widely used as in vitro models to study OL (dys) functioning. Here we applied a number of protocols aimed at differentiating HOG and MO3.13 cells into myOLs. However, none of the differentiation protocols led to increased expression of terminal OL differentiation or myelin-sheath formation markers. Surprisingly, the applied protocols did cause changes in the expression of markers for early OLs, neurons, astrocytes and Schwann cells. Furthermore, we noticed that mRNA expression levels in HOG and MO3.13 cells may be affected by the density of the cultured cells. Finally, HOG and MO3.13 co-cultured with human neuronal SH-SY5Y cells did not show myelin formation under several pro-OL-differentiation and pro-myelinating conditions. Together, our results illustrate the difficulty of inducing maturation of HOG and MO3.13 cells into myOLs, implying that these oligodendrocytic cell lines may not represent an appropriate model to study the (dys)functioning of human (my)OLs and OL-linked disease mechanisms. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Parkinson's Disease)

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18 pages, 5236 KiB

Open AccessArticle

Effects of Enteric Environmental Modification by Coffee Components on Neurodegeneration in Rotenone-Treated Mice

by Ikuko Miyazaki, Nami Isooka, Kouichi Wada, Ryo Kikuoka, Yoshihisa Kitamura and Masato Asanuma

Cells 2019, 8(3), 221; https://doi.org/10.3390/cells8030221 - 07 Mar 2019

Cited by 35 | Viewed by 10522

Abstract

Epidemiological studies have shown that coffee consumption decreases the risk of Parkinson’s disease (PD). Caffeic acid (CA) and chlorogenic acid (CGA) are coffee components that have antioxidative properties. Rotenone, a mitochondrial complex I inhibitor, has been used to develop parkinsonian models, because the toxin induces PD-like pathology. Here, we examined the neuroprotective effects of CA and CGA against the rotenone-induced degeneration of central dopaminergic and peripheral enteric neurons. Male C57BL/6J mice were chronically administered rotenone (2.5 mg/kg/day), subcutaneously for four weeks. The animals were orally administered CA or CGA daily for 1 week before rotenone exposure and during the four weeks of rotenone treatment. Administrations of CA or CGA prevented rotenone-induced neurodegeneration of both nigral dopaminergic and intestinal enteric neurons. CA and CGA upregulated the antioxidative molecules, metallothionein (MT)-1,2, in striatal astrocytes of rotenone-injected mice. Primary cultured mesencephalic or enteric cells were pretreated with CA or CGA for 24 h, and then further co-treated with a low dose of rotenone (1–5 nM) for 48 h. The neuroprotective effects and MT upregulation induced by CA and CGA in vivo were reproduced in cultured cells. Our data indicated that intake of coffee components, CA and CGA, enhanced the antioxidative properties of glial cells and prevents rotenone-induced neurodegeneration in both the brain and myenteric plexus. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Parkinson's Disease)

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Graphical abstract

14 pages, 8087 KiB

Open AccessFeature PaperArticle

Dynamics of Parkinson’s Disease Multimodal Complex Treatment in Germany from 2010–2016: Patient Characteristics, Access to Treatment, and Formation of Regional Centers

by Daniel Richter, Dirk Bartig, Siegfried Muhlack, Elke Hartelt, Raphael Scherbaum, Aristeides H. Katsanos, Thomas Müller, Wolfgang Jost, Georg Ebersbach, Ralf Gold, Christos Krogias and Lars Tönges

Cells 2019, 8(2), 151; https://doi.org/10.3390/cells8020151 - 11 Feb 2019

Cited by 27 | Viewed by 4324

Abstract

Parkinson’s disease (PD) is currently the world’s fastest-growing neurological disorder. It is characterized by motor and non-motor symptoms which progressively lead to significant clinical impairment, causing a high burden of disease. In addition to pharmacological therapies, various non-pharmacological treatment options are available. A well established and frequently used multiprofessional inpatient treatment concept in Germany is “Parkinson’s disease multimodal complex treatment” (PD-MCT) which involves physiotherapists, occupational therapists, speech therapists, and other specializations for the optimization of treatment in PD (ICD G20) and other Parkinsonian syndromes (ICD G21 and G23). In this study we analyze the PD-MCT characteristics of 55,141 PD inpatients who have been integrated into this therapy concept in Germany in the years 2010–2016. We demonstrate that PD-MCT is increasingly applied over this time period. Predominately, PD patients with advanced disease stage and motor fluctuations in age groups between 45 and 69 years were hospitalized. In terms of gender, more male than female patients were treated. PD-MCT is provided primarily in specialized hospitals with high patient numbers but a minor part of all therapies is performed in a rather large number of hospitals with each one treating only a few patients. Access to PD-MCT differs widely across regions, leading to significant migration of patients from underserved areas to PD-MCT centers–a development that should be considered when implementing such therapies in other countries. Furthermore, our data imply that despite the overall increase in PD-MCT treatments during the observational period, the restricted treatment accessibility may not adequately satisfy current patient’s need. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Parkinson's Disease)

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13 pages, 925 KiB

Open AccessFeature PaperArticle

Impairment of Motor Function Correlates with Neurometabolite and Brain Iron Alterations in Parkinson’s Disease

by Beate Pesch, Swaantje Casjens, Dirk Woitalla, Shalmali Dharmadhikari, David A. Edmondson, Maria Angela Samis Zella, Martin Lehnert, Anne Lotz, Lennard Herrmann, Siegfried Muhlack, Peter Kraus, Chien-Lin Yeh, Benjamin Glaubitz, Tobias Schmidt-Wilcke, Ralf Gold, Christoph van Thriel, Thomas Brüning, Lars Tönges and Ulrike Dydak

Cells 2019, 8(2), 96; https://doi.org/10.3390/cells8020096 - 29 Jan 2019

Cited by 20 | Viewed by 5576

Abstract

We took advantage of magnetic resonance imaging (MRI) and spectroscopy (MRS) as non-invasive methods to quantify brain iron and neurometabolites, which were analyzed along with other predictors of motor dysfunction in Parkinson’s disease (PD). Tapping hits, tremor amplitude, and the scores derived from part III of the Movement Disorder Society-Sponsored Revision of the Unified Parkinson Disease Rating Scale (MDS-UPDRS3 scores) were determined in 35 male PD patients and 35 controls. The iron-sensitive MRI relaxation rate R2* was measured in the globus pallidus and substantia nigra. γ-aminobutyric acid (GABA)-edited and short echo-time MRS was used for the quantification of neurometabolites in the striatum and thalamus. Associations of R2*, neurometabolites, and other factors with motor function were estimated with Spearman correlations and mixed regression models to account for repeated measurements (hands, hemispheres). In PD patients, R2* and striatal GABA correlated with MDS-UPDRS3 scores if not adjusted for age. Patients with akinetic-rigid PD subtype (N = 19) presented with lower creatine and striatal glutamate and glutamine (Glx) but elevated thalamic GABA compared to controls or mixed PD subtype. In PD patients, Glx correlated with an impaired dexterity when adjusted for covariates. Elevated myo-inositol was associated with more tapping hits and lower MDS-UPDRS3 scores. Our neuroimaging study provides evidence that motor dysfunction in PD correlates with alterations in brain iron and neurometabolites. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Parkinson's Disease)

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9 pages, 414 KiB

Open AccessArticle

Zonisamide Administration Improves Fatty Acid β-Oxidation in Parkinson’s Disease

by Shin-Ichi Ueno, Shinji Saiki, Motoki Fujimaki, Haruka Takeshige-Amano, Taku Hatano, Genko Oyama, Kei-Ichi Ishikawa, Akihiro Yamaguchi, Shuko Nojiri, Wado Akamatsu and Nobutaka Hattori

Cells 2019, 8(1), 14; https://doi.org/10.3390/cells8010014 - 29 Dec 2018

Cited by 6 | Viewed by 4452

Abstract

Although many experimental studies have shown the favorable effects of zonisamide on mitochondria using models of Parkinson’s disease (PD), the influence of zonisamide on metabolism in PD patients remains unclear. To assess metabolic status under zonisamide treatment in PD, we performed a pilot study using a comprehensive metabolome analysis. Plasma samples were collected for at least one year from 30 patients with PD: 10 without zonisamide medication and 20 with zonisamide medication. We performed comprehensive metabolome analyses of plasma with capillary electrophoresis time-of-flight mass spectrometry and liquid chromatography time-of-flight mass spectrometry. We also measured disease severity using Hoehn and Yahr (H&Y) staging and the Unified Parkinson’s Disease Rating Scale (UPDRS) motor section, and analyzed blood chemistry. In PD with zonisamide treatment, 15 long-chain acylcarnitines (LCACs) tended to be increased, of which four (AC(12:0), AC(12:1)-1, AC(16:1), and AC(16:2)) showed statistical significance. Of these, two LCACs (AC(16:1) and AC(16:2)) were also identified by partial least squares analysis. There was no association of any LCAC with age, disease severity, levodopa daily dose, or levodopa equivalent dose. Because an upregulation of LCACs implies improvement of mitochondrial β-oxidation, zonisamide might be beneficial for mitochondrial β-oxidation, which is suppressed in PD. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Parkinson's Disease)

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10 pages, 268 KiB

Open AccessArticle

Epigenetic Study in Parkinson’s Disease: A Pilot Analysis of DNA Methylation in Candidate Genes in Brain

by Luis Navarro-Sánchez, Beatriz Águeda-Gómez, Silvia Aparicio and Jordi Pérez-Tur

Cells 2018, 7(10), 150; https://doi.org/10.3390/cells7100150 - 26 Sep 2018

Cited by 22 | Viewed by 4392

Abstract

Efforts have been made to understand the pathophysiology of Parkinson’s disease (PD). A significant number of studies have focused on genetics, despite the fact that the described pathogenic mutations have been observed only in around 10% of patients; this observation supports the fact that PD is a multifactorial disorder. Lately, differences in miRNA expression, histone modification, and DNA methylation levels have been described, highlighting the importance of epigenetic factors in PD etiology. Taking all this into consideration, we hypothesized that an alteration in the level of methylation in PD-related genes could be related to disease pathogenesis, possibly due to alterations in gene expression. After analysing promoter regions of five PD-related genes in three brain regions by pyrosequencing, we observed some differences in DNA methylation levels (hypo and hypermethylation) in substantia nigra in some CpG dinucleotides that, possibly through an alteration in Sp1 binding, could alter their expression. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Parkinson's Disease)

Review

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16 pages, 636 KiB

Open AccessReview

Molecular Imaging of the Dopamine Transporter

by Giovanni Palermo and Roberto Ceravolo

Cells 2019, 8(8), 872; https://doi.org/10.3390/cells8080872 - 10 Aug 2019

Cited by 54 | Viewed by 7156

Abstract

Dopamine transporter (DAT) single-photon emission tomography (SPECT) with (123)Ioflupane is a widely used diagnostic tool for patients with suspected parkinsonian syndromes, as it assists with differentiating between Parkinson’s disease (PD) or atypical parkinsonisms and conditions without a presynaptic dopaminergic deficit such as essential tremor, vascular and drug-induced parkinsonisms. Recent evidence supports its utility as in vivo proof of degenerative parkinsonisms, and DAT imaging has been proposed as a potential surrogate marker for dopaminergic nigrostriatal neurons. However, the interpretation of DAT-SPECT imaging may be challenged by several factors including the loss of DAT receptor density with age and the effect of certain drugs on dopamine uptake. Furthermore, a clear, direct relationship between nigral loss and DAT decrease has been controversial so far. Striatal DAT uptake could reflect nigral neuronal loss once the loss exceeds 50%. Indeed, reduction of DAT binding seems to be already present in the prodromal stage of PD, suggesting both an early synaptic dysfunction and the activation of compensatory changes to delay the onset of symptoms. Despite a weak correlation with PD severity and progression, quantitative measurements of DAT binding at baseline could be used to predict the emergence of late-disease motor fluctuations and dyskinesias. This review addresses the possibilities and limitations of DAT-SPECT in PD and, focusing specifically on regulatory changes of DAT in surviving DA neurons, we investigate its role in diagnosis and its prognostic value for motor complications as disease progresses. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Parkinson's Disease)

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16 pages, 739 KiB

Open AccessReview

GBA, Gaucher Disease, and Parkinson’s Disease: From Genetic to Clinic to New Therapeutic Approaches

by Giulietta M. Riboldi and Alessio B. Di Fonzo

Cells 2019, 8(4), 364; https://doi.org/10.3390/cells8040364 - 19 Apr 2019

Cited by 166 | Viewed by 16665

Abstract

Parkinson’s disease (PD) is the second most common degenerative disorder. Although the disease was described more than 200 years ago, its pathogenetic mechanisms have not yet been fully described. In recent years, the discovery of the association between mutations of the GBA gene (encoding for the lysosomal enzyme glucocerebrosidase) and PD facilitated a better understating of this disorder. GBA mutations are the most common genetic risk factor of the disease. However, mutations of this gene can be found in different phenotypes, such as Gaucher’s disease (GD), PD, dementia with Lewy bodies (DLB) and rapid eye movements (REM) sleep behavior disorders (RBDs). Understanding the pathogenic role of this mutation and its different manifestations is crucial for geneticists and scientists to guide their research and to select proper cohorts of patients. Moreover, knowing the implications of the GBA mutation in the context of PD and the other associated phenotypes is also important for clinicians to properly counsel their patients and to implement their care. With the present review we aim to describe the genetic, clinical, and therapeutic features related to the mutation of the GBA gene. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Parkinson's Disease)

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17 pages, 1488 KiB

Open AccessReview

Mesenchymal Stem Cells-derived Exosomes: A New Possible Therapeutic Strategy for Parkinson’s Disease?

by Helena Vilaça-Faria, António J. Salgado and Fábio G. Teixeira

Cells 2019, 8(2), 118; https://doi.org/10.3390/cells8020118 - 02 Feb 2019

Cited by 94 | Viewed by 9815

Abstract

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder worldwide. Clinically, it is characterized by severe motor complications caused by a progressive degeneration of dopaminergic neurons (DAn) and dopamine loss. Current treatment is focused on mitigating the symptoms through administration of levodopa, rather than on preventing DAn damage. Therefore, the use and development of neuroprotective/disease-modifying strategies is an absolute need, which can lead to promising gains on PD translational research. Mesenchymal stem cells (MSCs)–derived exosomes have been proposed as a promising therapeutic tool, since it has been demonstrated that they can act as biological nanoparticles with beneficial effects in different pathological conditions, including PD. Thus, considering their potential protective action in lesioned sites, MSCs-derived exosomes might also be active modulators of the neuroregeneration processes, opening a door for their future use as therapeutical strategies in human clinical trials. Therefore, in this review, we analyze the current understanding of MSCs-derived exosomes as a new possible therapeutic strategy for PD, by providing an overview about the potential role of miRNAs in the cellular and molecular basis of PD. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Parkinson's Disease)

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20 pages, 304 KiB

Open AccessFeature PaperReview

Novel Immunotherapeutic Approaches to Target Alpha-Synuclein and Related Neuroinflammation in Parkinson’s Disease

by Maria Angela Samis Zella, Judith Metzdorf, Friederike Ostendorf, Fabian Maass, Siegfried Muhlack, Ralf Gold, Aiden Haghikia and Lars Tönges

Cells 2019, 8(2), 105; https://doi.org/10.3390/cells8020105 - 31 Jan 2019

Cited by 29 | Viewed by 6250

Abstract

The etiology of Parkinson’s disease (PD) is significantly influenced by disease-causing changes in the protein alpha-Synuclein (aSyn). It can trigger and promote intracellular stress and thereby impair the function of dopaminergic neurons. However, these damage mechanisms do not only extend to neuronal cells, but also affect most glial cell populations, such as astroglia and microglia, but also T lymphocytes, which can no longer maintain the homeostatic CNS milieu because they produce neuroinflammatory responses to aSyn pathology. Through precise neuropathological examination, molecular characterization of biomaterials, and the use of PET technology, it has been clearly demonstrated that neuroinflammation is involved in human PD. In this review, we provide an in-depth overview of the pathomechanisms that aSyn elicits in models of disease and focus on the affected glial cell and lymphocyte populations and their interaction with pathogenic aSyn species. The interplay between aSyn and glial cells is analyzed both in the basic research setting and in the context of human neuropathology. Ultimately, a strong rationale builds up to therapeutically reduce the burden of pathological aSyn in the CNS. The current antibody-based approaches to lower the amount of aSyn and thereby alleviate neuroinflammatory responses is finally discussed as novel therapeutic strategies for PD. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Parkinson's Disease)

12 pages, 1254 KiB

Open AccessReview

Are Proteinopathy and Oxidative Stress Two Sides of the Same Coin?

by Nihar J. Mehta, Praneet Kaur Marwah and David Njus

Cells 2019, 8(1), 59; https://doi.org/10.3390/cells8010059 - 16 Jan 2019

Cited by 7 | Viewed by 4883

Abstract

Parkinson’s disease, like other neurodegenerative diseases, exhibits two common features: Proteinopathy and oxidative stress, leading to protein aggregation and mitochondrial damage respectively. Because both protein aggregates and dysfunctional mitochondria are eliminated by autophagy, we suggest that inadequate clearance may couple the two phenomena. If a neuron’s autophagy machinery is overwhelmed, whether by excessive oxidative stress or by excessive protein aggregation, protein aggregates and dysfunctional mitochondria will both accumulate. Parkinson’s disease may provide a unique window into this because there is evidence that both sides contribute. Mutations amplifying the aggregation of α-synuclein are associated with Parkinson’s disease. Likewise, mutations in Parkin and PINK1, proteins involved in mitophagy, suggest that impaired mitochondrial clearance is also a contributing factor. Many have suggested that dopamine oxidation products lead to oxidative stress accounting for the dopaminergic selectivity of the disease. We have presented evidence for the specific involvement of hypochlorite-oxidized cysteinyl-dopamine (HOCD), a redox-cycling benzothiazine derivative. While toxins like 6-hydroxydopamine and 1-methyl-4-phenyl pyridinium (MPP+) have been used to study mitochondrial involvement in Parkinson’s disease, HOCD may provide a more physiologically relevant approach. Understanding the role of mitochondrial dysfunction and oxidative stress in Parkinson’s disease and their relation to α-synuclein proteinopathy is important to gain a full picture of the cause, especially for the great majority of cases which are idiopathic. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Parkinson's Disease)

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58 pages, 5029 KiB

Open AccessReview

The Role of Lipids in Parkinson’s Disease

by Helena Xicoy, Bé Wieringa and Gerard J. M. Martens

Cells 2019, 8(1), 27; https://doi.org/10.3390/cells8010027 - 07 Jan 2019

Cited by 142 | Viewed by 13021

Abstract

Parkinson’s disease (PD) is a neurodegenerative disease characterized by a progressive loss of dopaminergic neurons from the nigrostriatal pathway, formation of Lewy bodies, and microgliosis. During the past decades multiple cellular pathways have been associated with PD pathology (i.e., oxidative stress, endosomal-lysosomal dysfunction, endoplasmic reticulum stress, and immune response), yet disease-modifying treatments are not available. We have recently used genetic data from familial and sporadic cases in an unbiased approach to build a molecular landscape for PD, revealing lipids as central players in this disease. Here we extensively review the current knowledge concerning the involvement of various subclasses of fatty acyls, glycerolipids, glycerophospholipids, sphingolipids, sterols, and lipoproteins in PD pathogenesis. Our review corroborates a central role for most lipid classes, but the available information is fragmented, not always reproducible, and sometimes differs by sex, age or PD etiology of the patients. This hinders drawing firm conclusions about causal or associative effects of dietary lipids or defects in specific steps of lipid metabolism in PD. Future technological advances in lipidomics and additional systematic studies on lipid species from PD patient material may improve this situation and lead to a better appreciation of the significance of lipids for this devastating disease. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Parkinson's Disease)

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