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Preclinical and Clinical Genetics in Parkinson’s Disease
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Preclinical and Clinical Genetics in Parkinson’s Disease

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (31 May 2021) | Viewed by 36380

Special Issue Editors

Dr. Olga Corti

E-Mail Website
Guest Editor
Paris Brain Institute, Hôpital de la Pitié-Salpêtrière, 75013 Paris, France
Prof. Dr. Edgar Kramer

E-Mail Website
Guest Editor
Peninsula Medical School, Institute of Translational and Stratified Medicine, Faculty of Health, University of Plymouth, Plymouth PL4 8AA, UK
Interests: neurology; neuroscience; Parkinson's disease; dementia; clinical neuroscience; nervous system damage; signal transduction
Dr. Jaan-Olle Andressoo

E-Mail Website
Guest Editor
1. Translational Neuroscience, Faculty of Medicine, University of Helsinki, Yliopistonkatu 4, 00100 Helsinki, Finland
2. Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, 171 77 Stockholm, Sweden

Special Issue Information

After a decade of unsuccessful testing of drugs in clinical trials, which were supposed to prevent, hold, or cure Parkinson’s disease, the focus switched back to investigating the molecular causes and mechanisms leading to this devastating disease. The lack of knowledge about the detailed mechanism of the disease’s cause and progression seems to have hampered the development of successful clinical trials’ design, execution, and interpretation.

Currently, 20 genes are associated with Parkinson’s disease and 90 independent risk-associated variants have been described (Blauwendraat et al., Lancet 2019). The proteins encoded by these genes and the associated risk factors form a network with a multitude of crosstalk events and interactions. Although age is the largest risk factor for Parkinson’s disease, one large, or several small, alterations can lead to a significant change in the network that over time can cause the slow progressive degeneration of substantia nigra dopaminergic neurons and other cells in the brain.

This Special Issue will focus on work that highlights the current knowledge and the ongoing research in the field of Parkinson’s disease genetics and genetic Parkinson’s disease animal models in the clinical and preclinical setting. We are encouraging colleagues with experience in this topic to provide original research articles, reviews and short communications (data and news and views).

Dr. Olga Corti
Dr. Edgar Kramer
Dr. Jaan-Olle Andressoo
Guest Editors

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. Genes is an international peer-reviewed open access monthly 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 2600 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.

Keywords

  • Parkinson’s disease (PD)
  • Genetics of PD
  • Midbrain dopaminergic neurons
  • Animal models of PD
  • Clinical trials for PD
  • Genome-wide association studies (GWAS) for PD
  • Molecular signalling in PD
  • PD-associated protein networks
  • Crosstalk of PD linked proteins, RNAs, lipids, and chemicals

Published Papers (5 papers)

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Research

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16 pages, 3926 KiB  
Article
Administration of AAV-Alpha Synuclein NAC Antibody Improves Locomotor Behavior in Rats Overexpressing Alpha Synuclein
by Yun-Hsiang Chen, Kuo-Jen Wu, Wei Hsieh, Brandon K. Harvey, Barry J. Hoffer, Yun Wang and Seong-Jin Yu
Genes 2021, 12(6), 948; https://doi.org/10.3390/genes12060948 - 21 Jun 2021
Cited by 10 | Viewed by 3543
Abstract
Accumulation of α-Synuclein (αSyn) in nigral dopaminergic neurons is commonly seen in patients with Parkinson′s disease (PD). We recently reported that transduction of intracellular single-chain intrabody targeting the 53–87 amino acid residues of human αSyn by recombinant adeno associated viral vector (AAV-NAC32) downregulated [...] Read more.
Accumulation of α-Synuclein (αSyn) in nigral dopaminergic neurons is commonly seen in patients with Parkinson′s disease (PD). We recently reported that transduction of intracellular single-chain intrabody targeting the 53–87 amino acid residues of human αSyn by recombinant adeno associated viral vector (AAV-NAC32) downregulated αSyn protein in SH-SY5Y cells and rat brain. This study characterizes the behavioral phenotype and dopaminergic protection in animals receiving AAV-NAC32. Our results show that adult DAT-Cre rats selectively overexpress αSyn in nigra dopaminergic neurons after local administration of AAV-DIO-αSyn. These animals develop PD-like phenotype, including bradykinesia and loss of tyrosine hydroxylase (TH) immunoreactivity in substantia nigra pars compacta dorsal tier (SNcd). An injection of AAV-NAC32 to nigra produces a selective antibody against αSyn and normalizes the behavior. AAV-NAC32 significantly increases TH, while reduces αSyn immunoreactivity in SNcd. Altogether, our data suggest that an AAV-mediated gene transfer of NAC32 antibody effectively antagonizes αSyn-mediated dopaminergic degeneration in nigra, which may be a promising therapeutic candidate for synucleinopathy or PD. Full article
(This article belongs to the Special Issue Preclinical and Clinical Genetics in Parkinson’s Disease)
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Review

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44 pages, 1418 KiB  
Review
The Role of NEDD4 E3 Ubiquitin–Protein Ligases in Parkinson’s Disease
by James A. Conway, Grant Kinsman and Edgar R. Kramer
Genes 2022, 13(3), 513; https://doi.org/10.3390/genes13030513 - 14 Mar 2022
Cited by 11 | Viewed by 5188
Abstract
Parkinson’s disease (PD) is a debilitating neurodegenerative disease that causes a great clinical burden. However, its exact molecular pathologies are not fully understood. Whilst there are a number of avenues for research into slowing, halting, or reversing PD, one central idea is to [...] Read more.
Parkinson’s disease (PD) is a debilitating neurodegenerative disease that causes a great clinical burden. However, its exact molecular pathologies are not fully understood. Whilst there are a number of avenues for research into slowing, halting, or reversing PD, one central idea is to enhance the clearance of the proposed aetiological protein, oligomeric α-synuclein. Oligomeric α-synuclein is the main constituent protein in Lewy bodies and neurites and is considered neurotoxic. Multiple E3 ubiquitin-protein ligases, including the NEDD4 (neural precursor cell expressed developmentally downregulated protein 4) family, parkin, SIAH (mammalian homologues of Drosophila seven in absentia), CHIP (carboxy-terminus of Hsc70 interacting protein), and SCFFXBL5 SCF ubiquitin ligase assembled by the S-phase kinase-associated protein (SKP1), cullin-1 (Cul1), a zinc-binding RING finger protein, and the F-box domain/Leucine-rich repeat protein 5-containing protein FBXL5), have been shown to be able to ubiquitinate α-synuclein, influencing its subsequent degradation via the proteasome or lysosome. Here, we explore the link between NEDD4 ligases and PD, which is not only via α-synuclein but further strengthened by several additional substrates and interaction partners. Some members of the NEDD4 family of ligases are thought to crosstalk even with PD-related genes and proteins found to be mutated in familial forms of PD. Mutations in NEDD4 family genes have not been observed in PD patients, most likely because of their essential survival function during development. Following further in vivo studies, it has been thought that NEDD4 ligases may be viable therapeutic targets in PD. NEDD4 family members could clear toxic proteins, enhancing cell survival and slowing disease progression, or might diminish beneficial proteins, reducing cell survival and accelerating disease progression. Here, we review studies to date on the expression and function of NEDD4 ubiquitin ligases in the brain and their possible impact on PD pathology. Full article
(This article belongs to the Special Issue Preclinical and Clinical Genetics in Parkinson’s Disease)
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8 pages, 805 KiB  
Review
Genetically Targeted Clinical Trials in Parkinson’s Disease: Learning from the Successes Made in Oncology
by Magnus Sjögren, Henri J. Huttunen, Per Svenningsson and Håkan Widner
Genes 2021, 12(10), 1529; https://doi.org/10.3390/genes12101529 - 28 Sep 2021
Cited by 3 | Viewed by 2703
Abstract
Clinical trials in neurodegenerative disorders have been associated with high rate of failures, while in oncology, the implementation of precision medicine and focus on genetically defined subtypes of disease and targets for drug development have seen an unprecedented success. With more than 20 [...] Read more.
Clinical trials in neurodegenerative disorders have been associated with high rate of failures, while in oncology, the implementation of precision medicine and focus on genetically defined subtypes of disease and targets for drug development have seen an unprecedented success. With more than 20 genes associated with Parkinson’s disease (PD), most of which are highly penetrant and often cause early onset or atypical signs and symptoms, and an increasing understanding of the associated pathophysiology culminating in dopaminergic neurodegeneration, applying the technologies and designs into the field of neurodegeneration seems a logical step. This review describes some of the methods used in oncology clinical trials and some attempts in Parkinson’s disease and the potential of further implementing genetics, biomarkers and smart clinical trial designs in this disease area. Full article
(This article belongs to the Special Issue Preclinical and Clinical Genetics in Parkinson’s Disease)
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16 pages, 1310 KiB  
Review
Roles for α-Synuclein in Gene Expression
by Mahalakshmi Somayaji, Zina Lanseur, Se Joon Choi, David Sulzer and Eugene V. Mosharov
Genes 2021, 12(8), 1166; https://doi.org/10.3390/genes12081166 - 29 Jul 2021
Cited by 12 | Viewed by 4340
Abstract
α-Synuclein (α-Syn) is a small cytosolic protein associated with a range of cellular compartments, including synaptic vesicles, the nucleus, mitochondria, endoplasmic reticulum, Golgi apparatus, and lysosomes. In addition to its physiological role in regulating presynaptic function, the protein plays a central role in [...] Read more.
α-Synuclein (α-Syn) is a small cytosolic protein associated with a range of cellular compartments, including synaptic vesicles, the nucleus, mitochondria, endoplasmic reticulum, Golgi apparatus, and lysosomes. In addition to its physiological role in regulating presynaptic function, the protein plays a central role in both sporadic and familial Parkinson’s disease (PD) via a gain-of-function mechanism. Because of this, several recent strategies propose to decrease α-Syn levels in PD patients. While these therapies may offer breakthroughs in PD management, the normal functions of α-Syn and potential side effects of its depletion require careful evaluation. Here, we review recent evidence on physiological and pathological roles of α-Syn in regulating activity-dependent signal transduction and gene expression pathways that play fundamental role in synaptic plasticity. Full article
(This article belongs to the Special Issue Preclinical and Clinical Genetics in Parkinson’s Disease)
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23 pages, 638 KiB  
Review
The Genetics of Parkinson’s Disease and Implications for Clinical Practice
by Jacob Oliver Day and Stephen Mullin
Genes 2021, 12(7), 1006; https://doi.org/10.3390/genes12071006 - 30 Jun 2021
Cited by 73 | Viewed by 19751
Abstract
The genetic landscape of Parkinson’s disease (PD) is characterised by rare high penetrance pathogenic variants causing familial disease, genetic risk factor variants driving PD risk in a significant minority in PD cases and high frequency, low penetrance variants, which contribute a small increase [...] Read more.
The genetic landscape of Parkinson’s disease (PD) is characterised by rare high penetrance pathogenic variants causing familial disease, genetic risk factor variants driving PD risk in a significant minority in PD cases and high frequency, low penetrance variants, which contribute a small increase of the risk of developing sporadic PD. This knowledge has the potential to have a major impact in the clinical care of people with PD. We summarise these genetic influences and discuss the implications for therapeutics and clinical trial design. Full article
(This article belongs to the Special Issue Preclinical and Clinical Genetics in Parkinson’s Disease)
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