Editorial

5 pages, 205 KiB

Open AccessEditorial

Perspective: Is a Closer Interaction between Experimental and Clinical Research Paradigms in Chronic Neurodegeneration, Such as Parkinson’s Disease, Necessary Again?

by Thomas Müller

Cells 2023, 12(1), 157; https://doi.org/10.3390/cells12010157 - 30 Dec 2022

Cited by 1 | Viewed by 805

Abstract

This editorial discusses the current standstill in research in Parkinson’s disease from a clinician’s point of view [...] Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Parkinson's Disease 2019)

Research

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19 pages, 2628 KiB

Open AccessArticle

Interventional Influence of the Intestinal Microbiome Through Dietary Intervention and Bowel Cleansing Might Improve Motor Symptoms in Parkinson’s Disease

by Tobias Hegelmaier, Marco Lebbing, Alexander Duscha, Laura Tomaske, Lars Tönges, Jacob Bak Holm, Henrik Bjørn Nielsen, Sören G. Gatermann, Horst Przuntek and Aiden Haghikia

Cells 2020, 9(2), 376; https://doi.org/10.3390/cells9020376 - 06 Feb 2020

Cited by 55 | Viewed by 7836

Abstract

The impact of the gut microbiome is being increasingly appreciated in health and in various chronic diseases, among them neurodegenerative disorders such as Parkinson’s disease (PD). In the pathogenesis of PD, the role of the gut has been previously established. In conjunction with [...] Read more.

The impact of the gut microbiome is being increasingly appreciated in health and in various chronic diseases, among them neurodegenerative disorders such as Parkinson’s disease (PD). In the pathogenesis of PD, the role of the gut has been previously established. In conjunction with a better understanding of the intestinal microbiome, a link to the misfolding and spread of alpha-synuclein via inflammatory processes within the gut is discussed. In a case-control study, we assessed the gut microbiome of 54 PD patients and 32 healthy controls (HC). Additionally, we tested in this proof-of-concept study whether dietary intervention alone or additional physical colon cleaning may lead to changes of the gut microbiome in PD. 16 PD patients underwent a well-controlled balanced, ovo-lacto vegetarian diet intervention including short fatty acids for 14 days. 10 of those patients received additional treatment with daily fecal enema over 8 days. Stool samples were collected before and after 14 days of intervention. In comparison to HC, we could confirm previously reported PD associated microbiome changes. The UDPRS III significantly improved and the levodopa-equivalent daily dose decreased after vegetarian diet and fecal enema in a one-year follow-up. Additionally, we observed a significant association between the gut microbiome diversity and the UPDRS III and the abundance of Ruminococcaceae. Additionally, the abundance of Clostridiaceae was significantly reduced after enema. Dietary intervention and bowel cleansing may provide an additional non-pharmacologic therapeutic option for PD patients. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Parkinson's Disease 2019)

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17 pages, 3692 KiB

Open AccessArticle

Blood Contamination in CSF and Its Impact on Quantitative Analysis of Alpha-Synuclein

by Katalin Barkovits, Niels Kruse, Andreas Linden, Lars Tönges, Kathy Pfeiffer, Brit Mollenhauer and Katrin Marcus

Cells 2020, 9(2), 370; https://doi.org/10.3390/cells9020370 - 05 Feb 2020

Cited by 28 | Viewed by 4705

Abstract

Analysis of cerebrospinal fluid (CSF) is important for diagnosis of neurological diseases. Especially for neurodegenerative diseases, abnormal protein abundance in CSF is an important biomarker. However, the quality of CSF is a key factor for the analytic outcome. Any external contamination has tremendous [...] Read more.

Analysis of cerebrospinal fluid (CSF) is important for diagnosis of neurological diseases. Especially for neurodegenerative diseases, abnormal protein abundance in CSF is an important biomarker. However, the quality of CSF is a key factor for the analytic outcome. Any external contamination has tremendous impact on the analysis and the reliability of the results. In this study, we evaluated the effect of blood contamination in CSF with respect to protein biomarker identification. We compared three distinct measures: Combur10-Test^® strips, a specific hemoglobin ELISA, and bottom-up mass spectrometry (MS)-based proteomics for the determination of the general blood contamination level. In parallel, we studied the impact of blood contamination on the detectability of alpha-synuclein (aSyn), a highly abundant protein in blood/erythrocytes and a potential biomarker for Parkinson’s disease. Comparable results were achieved, with all three approaches enabling detection of blood levels in CSF down to 0.001%. We found higher aSyn levels with increasing blood contamination, highlighting the difficulty of authentic quantification of this protein in CSF. Based on our results, we identified other markers for blood contamination beyond hemoglobin and defined a grading system for blood levels in CSF samples, including a lower limit of tolerable blood contamination for MS-based biomarker studies. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Parkinson's Disease 2019)

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9 pages, 1246 KiB

Open AccessArticle

Lentiform Nucleus Hyperechogenicity in Parkinsonian Syndromes: A Systematic Review and Meta-Analysis with Consideration of Molecular Pathology

by Daniel Richter, Aristeidis H. Katsanos, Christoph Schroeder, Georgios Tsivgoulis, George P. Paraskevas, Thomas Müller, Andrei V. Alexandrov, Ralf Gold, Lars Tönges and Christos Krogias

Cells 2020, 9(1), 2; https://doi.org/10.3390/cells9010002 - 18 Dec 2019

Cited by 9 | Viewed by 2564

Abstract

The hyperechogenicity of the substania nigra (SN) has been established as a valid finding in patients with Parkinson’s disease (PD), probably caused by an increased tissue iron concentration in the SN. The application of transcranial sonography (TCS) has been investigated for further echogenic [...] Read more.

The hyperechogenicity of the substania nigra (SN) has been established as a valid finding in patients with Parkinson’s disease (PD), probably caused by an increased tissue iron concentration in the SN. The application of transcranial sonography (TCS) has been investigated for further echogenic basal ganglia alterations in patients with extrapyramidal movement disorders. Compared to PD, a hyperechogenic nucleus lentiformis (LN) has been reported to appear more frequently in atypical parkinsonian syndromes (aPS) such as the parkinsonian phenotype of multiple system atrophy (MSA-P) or the progressive supranuclear palsy (PSP). As the evidence providing study sizes are small, we conduct the first meta-analysis of the prevalence of LN hyperechogenicity in PD and aPS. We search for available studies providing prevalence of LN hyperechogenicity in patients with PD and aPS (MSA-P and PSP) detected by TCS in MEDLINE and SCOPUS databases. We calculate the prevalence rates of LN hyperechogenicity detection in patients with clinical diagnosis of PD vs. aPS under the random-effects model. We include a total of 1330 patients, 1091 PD and 239 aPS (MSA-P and PSP). We find a significantly higher prevalence of LN hyperechogenicity in aPS (76%, 95% CI: 0.62-0.88) compared to PD (16%, 95% CI: 0.10-0.23). After proving a higher prevalence of LN hyperechogenicity in aPS compared to PD, its histopathological cause needs to be investigated. Furthermore, its full diagnostic accuracy and the qualification to serve as a risk factor for MSA-P and PSP should also be questioned in future studies. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Parkinson's Disease 2019)

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24 pages, 9180 KiB

Open AccessArticle

The Therapeutic Implications of Tea Polyphenols against Dopamine (DA) Neuron Degeneration in Parkinson’s Disease (PD)

by Zhi Dong Zhou, Shao Ping Xie, Wuan Ting Saw, Patrick Ghim Hoe Ho, Hong Yan Wang, Lei Zhou, Yi Zhao and Eng King Tan

Cells 2019, 8(8), 911; https://doi.org/10.3390/cells8080911 - 16 Aug 2019

Cited by 76 | Viewed by 6033

Abstract

Accumulative evidence indicated that the pathologically accumulated metal ions (iron species and Mn³⁺) and abnormally up-regulated monoamine oxidase B (MAOB) activity induced oxidation of endogenous dopamine (DA) can lead to mitochondria impairment, lysosome dysfunction, proteasome inhibition, and selective DA neuron vulnerability, [...] Read more.

Accumulative evidence indicated that the pathologically accumulated metal ions (iron species and Mn³⁺) and abnormally up-regulated monoamine oxidase B (MAOB) activity induced oxidation of endogenous dopamine (DA) can lead to mitochondria impairment, lysosome dysfunction, proteasome inhibition, and selective DA neuron vulnerability, which is implicated in the pathogenesis of Parkinson’s disease (PD). The DA oxidation can generate deleterious reactive oxygen species (ROS) and highly reactive DA quinones (DAQ) to induce DA-related toxicity, which can be alleviated by DA oxidation suppressors, ROS scavengers, DAQ quenchers, and MAOB inhibitors. On the other hand, the nuclear factor erythroid 2-related factor 2 (Nrf2)-Keap1 and Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) anti-oxidative and proliferative signaling pathways play roles in anti-oxidative cell defense and mitochondria biogenesis, which is implicated in DA neuron protections. Therefore, agents with capabilities to suppress DA-related toxicity including inhibition of DA oxidation, scavenge of ROS, detoxification of DAQ, inhibition of MAOB, and modulations of anti-oxidative signaling pathways can be protective to DA neurons. Accumulative evidence shows that tea or coffee consumptions and smoking are related to deceased PD prevalence with unknown mechanisms. In this study, we investigate the protective capabilities of tea polyphenols and other PD relevant agents to inhibit DA-related toxicity and protect against environmental or genetic factors induced DA neuron degeneration in vitro and in vivo. We find that tea polyphenols can significantly suppress DA-related toxicity to protect DA neurons. The tea polyphenols can protect DA neurons via inhibition of DA oxidation, conjugation with DAQ, scavenge of ROS, inhibition of MAOB, and modulations of Nrf2-Keap1 and PGC-1α anti-oxidative signaling pathways. The tea polyphenols with more phenolic hydroxyl groups and ring structures have stronger protective functions. The protective capabilities of tea polyphenols is further strengthened by evidence that phenolic hydroxyl groups can directly conjugate with DAQ. However, GSH and other sulfhydyl groups containing agents have weaker capabilities to abrogate DA oxidation, detoxify ROS and DAQ and inhibit MAOB; whereas nicotine (NICO) and caffeine (CAF) can only modulate Nrf2-Keap1 and PGC-1α pathways to protect DA neurons weakly. The tea polyphenols are identified to protect against overexpression of mutant A30P α-synuclein (α-syn) induced DA neuron degeneration and PD-like symptoms in transgenic Drosophila. Based on achievements from current studies, the excellent and versatile protective capabilities of tea polyphenols are highlighted, which will contribute and benefit to future anti-PD therapy. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Parkinson's Disease 2019)

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13 pages, 28936 KiB

Open AccessArticle

Melanin and Neuromelanin Fluorescence Studies Focusing on Parkinson’s Disease and Its Inherent Risk for Melanoma

by Dieter Leupold, Lukasz Szyc, Goran Stankovic, Sabrina Strobel, Hans-Ullrich Völker, Ulrike Fleck, Thomas Müller, Matthias Scholz, Peter Riederer and Camelia-Maria Monoranu

Cells 2019, 8(6), 592; https://doi.org/10.3390/cells8060592 - 15 Jun 2019

Cited by 7 | Viewed by 4656

Abstract

Parkinson’s disease is associated with an increased risk of melanoma (and vice versa). Several hypotheses underline this link, such as pathways affecting both melanin and neuromelanin. For the first time, the fluorescence of melanin and neuromelanin is selectively accessible using a new method [...] Read more.

Parkinson’s disease is associated with an increased risk of melanoma (and vice versa). Several hypotheses underline this link, such as pathways affecting both melanin and neuromelanin. For the first time, the fluorescence of melanin and neuromelanin is selectively accessible using a new method of nonlinear spectroscopy, based on a stepwise two-photon excitation. Cutaneous pigmentation and postmortem neuromelanin of Parkinson patients were characterized by fluorescence spectra and compared with controls. Spectral differences could not be documented, implying that there is neither a Parkinson fingerprint in cutaneous melanin spectra nor a melanin-associated fingerprint indicating an increased melanoma risk. Our measurements suggest that Parkinson’s disease occurs without a configuration change of neuromelanin. However, Parkinson patients displayed the same dermatofluorescence spectroscopic fingerprint of a local malignant transformation as controls. This is the first comparative retrospective fluorescence analysis of cutaneous melanin and postmortem neuromelanin based on nonlinear spectroscopy in patients with Parkinson’s disease and controls, and this method is a very suitable diagnostic tool for melanoma screening and early detection in Parkinson patients. Our results suggest a non-pigmentary pathway as the main link between Parkinson’s disease and melanoma, and they do not rule out the melanocortin-1-receptor gene as an additional bridge between both diseases. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Parkinson's Disease 2019)

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22 pages, 2131 KiB

Open AccessFeature PaperArticle

Synergistic Effect of Mitochondrial and Lysosomal Dysfunction in Parkinson’s Disease

by Flora Guerra, Giulia Girolimetti, Raffaella Beli, Marco Mitruccio, Consiglia Pacelli, Anna Ferretta, Giuseppe Gasparre, Tiziana Cocco and Cecilia Bucci

Cells 2019, 8(5), 452; https://doi.org/10.3390/cells8050452 - 14 May 2019

Cited by 38 | Viewed by 7804

Abstract

Crosstalk between lysosomes and mitochondria plays a central role in Parkinson’s Disease (PD). Lysosomal function may be influenced by mitochondrial quality control, dynamics and/or respiration, but whether dysfunction of endocytic or autophagic pathway is associated with mitochondrial impairment determining accumulation of defective mitochondria, [...] Read more.

Crosstalk between lysosomes and mitochondria plays a central role in Parkinson’s Disease (PD). Lysosomal function may be influenced by mitochondrial quality control, dynamics and/or respiration, but whether dysfunction of endocytic or autophagic pathway is associated with mitochondrial impairment determining accumulation of defective mitochondria, is not yet understood. Here, we performed live imaging, western blotting analysis, sequencing of mitochondrial DNA (mtDNA) and senescence-associated beta-galactosidase activity assay on primary fibroblasts from a young patient affected by PD, her mother and a healthy control to analyze the occurrence of mtDNA mutations, lysosomal abundance, acidification and function, mitochondrial biogenesis activation and senescence. We showed synergistic alterations in lysosomal functions and mitochondrial biogenesis, likely associated with a mitochondrial genetic defect, with a consequent block of mitochondrial turnover and occurrence of premature cellular senescence in PARK2-PD fibroblasts, suggesting that these alterations represent potential mechanisms contributing to the loss of dopaminergic neurons. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Parkinson's Disease 2019)

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15 pages, 7473 KiB

Open AccessFeature PaperArticle

Gait Training in Virtual Reality: Short-Term Effects of Different Virtual Manipulation Techniques in Parkinson’s Disease

by Omar Janeh, Odette Fründt, Beate Schönwald, Alessandro Gulberti, Carsten Buhmann, Christian Gerloff, Frank Steinicke and Monika Pötter-Nerger

Cells 2019, 8(5), 419; https://doi.org/10.3390/cells8050419 - 06 May 2019

Cited by 40 | Viewed by 6615

Abstract

It is well documented that there is a strong relationship between gait asymmetry and the freezing of gait (FOG) in Parkinson’s Disease. The purpose of this pilot study was to find a “virtual reality (VR)- based” gait manipulation strategy to improve gait symmetry [...] Read more.

It is well documented that there is a strong relationship between gait asymmetry and the freezing of gait (FOG) in Parkinson’s Disease. The purpose of this pilot study was to find a “virtual reality (VR)- based” gait manipulation strategy to improve gait symmetry by equalizing step length. Fifteen male PD patients (mean age of 67.6 years) with FOG were assessed on a GAITRite^® walkway. Natural gait was compared with walking conditions during “VR-based” gait modulation tasks that aimed at equalizing gait symmetry using visual or proprioceptive signals. Compared to natural gait, VR manipulation tasks significantly increased step width and swing time variability for both body sides. Within the VR conditions, only the task with “proprioceptive-visual dissociation” by artificial backward shifting of the foot improved spatial asymmetry significantly with comparable step lengths of both sides. Specific, hypothesis-driven VR tasks represent an efficient tool to manipulate gait features as gait symmetry in PD potentially preventing FOG. This pilot study offers promising “VR-based” approaches for rehabilitative training strategies to achieve gait symmetry and prevent FOG. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Parkinson's Disease 2019)

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Review

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29 pages, 1835 KiB

Open AccessReview

Cellular and Synaptic Dysfunctions in Parkinson’s Disease: Stepping Out of the Striatum

by Nicolas Mallet, Lorena Delgado, Marine Chazalon, Cristina Miguelez and Jérôme Baufreton

Cells 2019, 8(9), 1005; https://doi.org/10.3390/cells8091005 - 29 Aug 2019

Cited by 49 | Viewed by 12241

Abstract

The basal ganglia (BG) are a collection of interconnected subcortical nuclei that participate in a great variety of functions, ranging from motor programming and execution to procedural learning, cognition, and emotions. This network is also the region primarily affected by the degeneration of [...] Read more.

The basal ganglia (BG) are a collection of interconnected subcortical nuclei that participate in a great variety of functions, ranging from motor programming and execution to procedural learning, cognition, and emotions. This network is also the region primarily affected by the degeneration of midbrain dopaminergic neurons localized in the substantia nigra pars compacta (SNc). This degeneration causes cellular and synaptic dysfunctions in the BG network, which are responsible for the appearance of the motor symptoms of Parkinson’s disease. Dopamine (DA) modulation and the consequences of its loss on the striatal microcircuit have been extensively studied, and because of the discrete nature of DA innervation of other BG nuclei, its action outside the striatum has been considered negligible. However, there is a growing body of evidence supporting functional extrastriatal DA modulation of both cellular excitability and synaptic transmission. In this review, the functional relevance of DA modulation outside the striatum in both normal and pathological conditions will be discussed. Full article

(This article belongs to the Special Issue The Molecular and Cellular Basis for Parkinson's Disease 2019)

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