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The Molecular and Cellular Basis for Parkinson’s Disease 2021
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The Molecular and Cellular Basis for Parkinson’s Disease 2021

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

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 17578

Special Issue Editor

Prof. Dr. Thomas Müller

E-Mail Website
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.

You may choose our Joint Special Issue

https://www.mdpi.com/journal/biomolecules/special_issues/Molecular_Parkinson_Disease_2021

https://www.mdpi.com/journal/neurosci/special_issues/Parkinson_Disease_2021

in Biomolecules and NeuroSci.

Dr. Thomas Müller
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (5 papers)

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Research

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13 pages, 2020 KiB  
Article
Unexpected Implication of SRP and AGO2 in Parkinson’s Disease: Involvement in Alpha-Synuclein Biogenesis
by Sarah M. Hernandez, Elena B. Tikhonova, Kristen R. Baca, Fanpeng Zhao, Xiongwei Zhu and Andrey L. Karamyshev
Cells 2021, 10(10), 2792; https://doi.org/10.3390/cells10102792 - 18 Oct 2021
Cited by 9 | Viewed by 2128
Abstract
Parkinson’s disease (PD) is a neurodegenerative disorder classified by the loss of dopaminergic neurons in the substantia nigra pars compacta, the region of the brain that is responsible for motor control. Surviving neurons in this region contain aggregated protein alpha-Synuclein (αSyn) in the [...] Read more.
Parkinson’s disease (PD) is a neurodegenerative disorder classified by the loss of dopaminergic neurons in the substantia nigra pars compacta, the region of the brain that is responsible for motor control. Surviving neurons in this region contain aggregated protein alpha-Synuclein (αSyn) in the form of cytoplasmic inclusions, referred to as Lewy bodies. Changes in αSyn expression are also associated with PD and its progression. Previously, we demonstrated that signal recognition particle (SRP) and Argonaute 2 (AGO2) proteins are involved in protein quality control at the ribosome during translation. We also demonstrated that SRP has an mRNA protection function in addition to a protein targeting function, thus controlling mRNA and protein expression. In this study, we tested involvement of these factors in αSyn biogenesis. We hypothesize that loss of these factors may interfere with αSyn expression, and subsequently, be associated with PD. Using depletion assays in human cell culture and analysis of these proteins in the brains of deceased PD patients, we demonstrate that SRP and AGO2 are involved in the control of αSyn expression and AGO2 has reduced expression in PD. We show for the first time that SRP is involved in mRNA protection of αSyn, a protein that does not have a signal sequence or transmembrane span. Our findings suggest that SRP may interact with a hydrophobic domain in the middle of αSyn during translation. Understanding the molecular mechanisms controlling αSyn biogenesis in cells is vital to developing preventative therapies against PD. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis for Parkinson’s Disease 2021)
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Review

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16 pages, 1672 KiB  
Review
Clinical Sphingolipids Pathway in Parkinson’s Disease: From GCase to Integrated-Biomarker Discovery
by Ali Esfandiary, David Isaac Finkelstein, Nicolas Hans Voelcker and David Rudd
Cells 2022, 11(8), 1353; https://doi.org/10.3390/cells11081353 - 15 Apr 2022
Cited by 7 | Viewed by 3302
Abstract
Alterations in the sphingolipid metabolism of Parkinson’s Disease (PD) could be a potential diagnostic feature. Only around 10–15% of PD cases can be diagnosed through genetic alterations, while the remaining population, idiopathic PD (iPD), manifest without validated and specific biomarkers either before or [...] Read more.
Alterations in the sphingolipid metabolism of Parkinson’s Disease (PD) could be a potential diagnostic feature. Only around 10–15% of PD cases can be diagnosed through genetic alterations, while the remaining population, idiopathic PD (iPD), manifest without validated and specific biomarkers either before or after motor symptoms appear. Therefore, clinical diagnosis is reliant on the skills of the clinician, which can lead to misdiagnosis. IPD cases present with a spectrum of non-specific symptoms (e.g., constipation and loss of the sense of smell) that can occur up to 20 years before motor function loss (prodromal stage) and formal clinical diagnosis. Prodromal alterations in metabolites and proteins from the pathways underlying these symptoms could act as biomarkers if they could be differentiated from the broad values seen in a healthy age-matched control population. Additionally, these shifts in metabolites could be integrated with other emerging biomarkers/diagnostic tests to give a PD-specific signature. Here we provide an up-to-date review of the diagnostic value of the alterations in sphingolipids pathway in PD by focusing on the changes in definitive PD (postmortem confirmed brain data) and their representation in “probable PD” cerebrospinal fluid (CSF) and blood. We conclude that the trend of holistic changes in the sphingolipid pathway in the PD brain seems partly consistent in CSF and blood, and could be one of the most promising pathways in differentiating PD cases from healthy controls, with the potential to improve early-stage iPD diagnosis and distinguish iPD from other Parkinsonism when combined with other pathological markers. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis for Parkinson’s Disease 2021)
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19 pages, 713 KiB  
Review
Disruption of Mitochondrial Homeostasis: The Role of PINK1 in Parkinson’s Disease
by Maria Vizziello, Linda Borellini, Giulia Franco and Gianluca Ardolino
Cells 2021, 10(11), 3022; https://doi.org/10.3390/cells10113022 - 04 Nov 2021
Cited by 19 | Viewed by 4229
Abstract
The progressive reduction of the dopaminergic neurons of the substantia nigra is the fundamental process underlying Parkinson’s disease (PD), while the mechanism of susceptibility of this specific neuronal population is largely unclear. Disturbances in mitochondrial function have been recognized as one of the [...] Read more.
The progressive reduction of the dopaminergic neurons of the substantia nigra is the fundamental process underlying Parkinson’s disease (PD), while the mechanism of susceptibility of this specific neuronal population is largely unclear. Disturbances in mitochondrial function have been recognized as one of the main pathways in sporadic PD since the finding of respiratory chain impairment in animal models of PD. Studies on genetic forms of PD have provided new insight on the role of mitochondrial bioenergetics, homeostasis, and autophagy. PINK1 (PTEN-induced putative kinase 1) gene mutations, although rare, are the second most common cause of recessively inherited early-onset PD, after Parkin gene mutations. Our knowledge of PINK1 and Parkin function has increased dramatically in the last years, with the discovery that a process called mitophagy, which plays a key role in the maintenance of mitochondrial health, is mediated by the PINK1/Parkin pathway. In vitro and in vivo models have been developed, supporting the role of PINK1 in synaptic transmission, particularly affecting dopaminergic neurons. It is of paramount importance to further define the role of PINK1 in mitophagy and mitochondrial homeostasis in PD pathogenesis in order to delineate novel therapeutic targets. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis for Parkinson’s Disease 2021)
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16 pages, 731 KiB  
Review
Perspective: Treatment for Disease Modification in Chronic Neurodegeneration
by Thomas Müller, Bernhard Klaus Mueller and Peter Riederer
Cells 2021, 10(4), 873; https://doi.org/10.3390/cells10040873 - 12 Apr 2021
Cited by 12 | Viewed by 2718
Abstract
Symptomatic treatments are available for Parkinson’s disease and Alzheimer’s disease. An unmet need is cure or disease modification. This review discusses possible reasons for negative clinical study outcomes on disease modification following promising positive findings from experimental research. It scrutinizes current research paradigms [...] Read more.
Symptomatic treatments are available for Parkinson’s disease and Alzheimer’s disease. An unmet need is cure or disease modification. This review discusses possible reasons for negative clinical study outcomes on disease modification following promising positive findings from experimental research. It scrutinizes current research paradigms for disease modification with antibodies against pathological protein enrichment, such as α-synuclein, amyloid or tau, based on post mortem findings. Instead a more uniform regenerative and reparative therapeutic approach for chronic neurodegenerative disease entities is proposed with stimulation of an endogenously existing repair system, which acts independent of specific disease mechanisms. The repulsive guidance molecule A pathway is involved in the regulation of peripheral and central neuronal restoration. Therapeutic antagonism of repulsive guidance molecule A reverses neurodegeneration according to experimental outcomes in numerous disease models in rodents and monkeys. Antibodies against repulsive guidance molecule A exist. First clinical studies in neurological conditions with an acute onset are under way. Future clinical trials with these antibodies should initially focus on well characterized uniform cohorts of patients. The efficiency of repulsive guidance molecule A antagonism and associated stimulation of neurogenesis should be demonstrated with objective assessment tools to counteract dilution of therapeutic effects by subjectivity and heterogeneity of chronic disease entities. Such a research concept will hopefully enhance clinical test strategies and improve the future therapeutic armamentarium for chronic neurodegeneration. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis for Parkinson’s Disease 2021)
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22 pages, 1749 KiB  
Review
The Importance of Drosophila melanogaster Research to UnCover Cellular Pathways Underlying Parkinson’s Disease
by Melissa Vos and Christine Klein
Cells 2021, 10(3), 579; https://doi.org/10.3390/cells10030579 - 06 Mar 2021
Cited by 17 | Viewed by 4165
Abstract
Parkinson’s disease (PD) is a complex neurodegenerative disorder that is currently incurable. As a consequence of an incomplete understanding of the etiology of the disease, therapeutic strategies mainly focus on symptomatic treatment. Even though the majority of PD cases remain idiopathic (~90%), several [...] Read more.
Parkinson’s disease (PD) is a complex neurodegenerative disorder that is currently incurable. As a consequence of an incomplete understanding of the etiology of the disease, therapeutic strategies mainly focus on symptomatic treatment. Even though the majority of PD cases remain idiopathic (~90%), several genes have been identified to be causative for PD, facilitating the generation of animal models that are a good alternative to study disease pathways and to increase our understanding of the underlying mechanisms of PD. Drosophila melanogaster has proven to be an excellent model in these studies. In this review, we will discuss the different PD models in flies and key findings identified in flies in different affected pathways in PD. Several molecular changes have been identified, of which mitochondrial dysfunction and a defective endo-lysosomal pathway emerge to be the most relevant for PD pathogenesis. Studies in flies have significantly contributed to our knowledge of how disease genes affect and interact in these pathways enabling a better understanding of the disease etiology and providing possible therapeutic targets for the treatment of PD, some of which have already resulted in clinical trials. Full article
(This article belongs to the Special Issue The Molecular and Cellular Basis for Parkinson’s Disease 2021)
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