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Understanding the Role of Non-coding DNA in Neurodegenerative Disease

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 March 2024) | Viewed by 3183

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Special Issue Editor

Prof. Dr. John P. Quinn

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Guest Editor

Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3BX, UK
Interests: gene expression; motor neurone disease; Parkinson’s disease; retrotransposons; genomics; nature vs nurture; regulatory RNA
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Special Issue Information

Dear Colleagues,

The non-coding genome orchestrates chromatin structure and function, replication, gene expression, and genome stability and integrity. It senses and responds to environmental challenges to modulate neuronal and non-neuronal cellular phenotypes at several levels, including epigenetic, transcriptional, and post-transcriptional mechanisms. The importance of the central role of non-coding DNA driving neurodegeneration is captured by the identification of numerous polymorphic domains in non-coding DNA from analysis of GWAS and other studies directed at genomic structural variants being significantly associated with risk and progression for many neurodegenerative conditions. Our understanding of the mechanisms operating at these variants is aided not only by molecular studies but also by the application of bioinformatics and machine-learning approaches to large data sets. In addition to the direct effect of DNA on genomic regulation, the non-coding DNA directs the generation of regulatory RNA of which there are many different classes with distinct roles in neurodegeneration. We would like to cover this range of diverse functions of the non-coding genome in a Special Issue of IJMS, “Understanding the role of non-coding DNA in Neurodegenerative Disease”. It will include a selection of original research articles, current review articles, and communications examining how non-coding DNA is a driving force behind cellular changes underpinning neurodegeneration.

Authors from all neurodegeneration diseases and areas are welcome. All regulatory mechanisms will be considered demonstrating the wealth and diversity in the modulation of cellular signaling, chromatin 3D organization, and gene expression driving cellular phenotypic changes in both neuronal and neuronal cells associated with neurodegeneration.

Prof. Dr. John P. Quinn
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

genomics
polymorphism
chromatin
epigenetics
neurodegenerative risk
neurodegenerative progression
cellular signaling
transcriptome
bioinformatics
chromosome structure

Published Papers (3 papers)

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Research

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9 pages, 400 KiB

Open AccessArticle

Evaluating the Classification Accuracy of Expression Quantitative Trait Loci Calculated Polygenic Risk Scores in Alzheimer’s Disease

by Keeley J. Brookes

Int. J. Mol. Sci. 2023, 24(16), 12799; https://doi.org/10.3390/ijms241612799 - 14 Aug 2023

Cited by 1 | Viewed by 991

Abstract

Polygenic risk scores (PRS) hold promise for the early identification of those at risk from neurodegenerative disorders such as Alzheimer’s Disease (AD), allowing for intervention to occur prior to neuronal damage. The current selection of informative single nucleotide polymorphisms (SNPs) to generate the risk scores is based on the modelling of large genome-wide association data using significance thresholds. However, the biological relevance of these SNPs is largely unknown. This study, in contrast, aims to identify SNPs with biological relevance to AD and then assess them for their ability to accurately classify cases and controls. Samples selected from the Brains for Dementia Research (BDR) were used to produce gene expression data to identify potential expression quantitative trait loci (eQTLs) relevant to AD. These SNPs were then incorporated into a PRS model to classify AD and controls in the full BDR cohort. Models derived from these eQTLs demonstrate modest classification potential with an accuracy between 61% and 67%. Although the model accuracy is not as high as some values in the literature based on significance thresholds from genome-wide association studies, these models may reflect a more biologically relevant model, which may provide novel targets for therapeutic intervention. Full article

(This article belongs to the Special Issue Understanding the Role of Non-coding DNA in Neurodegenerative Disease)

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16 pages, 3500 KiB

Open AccessArticle

A Genome-Wide Screen for the Exonisation of Reference SINE-VNTR-Alus and Their Expression in CNS Tissues of Individuals with Amyotrophic Lateral Sclerosis

by Abigail L. Pfaff, Vivien J. Bubb, John P. Quinn and Sulev Koks

Int. J. Mol. Sci. 2023, 24(14), 11548; https://doi.org/10.3390/ijms241411548 - 17 Jul 2023

Cited by 1 | Viewed by 1223

Abstract

The hominid-specific retrotransposon SINE-VNTR-Alu (SVA) is a composite element that has contributed to the genetic variation between individuals and influenced genomic structure and function. SVAs are involved in modulating gene expression and splicing patterns, altering mRNA levels and sequences, and have been associated with the development of disease. We evaluated the genome-wide effects of SVAs present in the reference genome on transcript sequence and expression in the CNS of individuals with and without the neurodegenerative disorder Amyotrophic Lateral Sclerosis (ALS). This study identified SVAs in the exons of 179 known transcripts, several of which were expressed in a tissue-specific manner, as well as 92 novel exonisation events occurring in the motor cortex. An analysis of 65 reference genome SVAs polymorphic for their presence/absence in the ALS consortium cohort did not identify any elements that were significantly associated with disease status, age at onset, and survival. However, there were transcripts, such as transferrin and HLA-A, that were differentially expressed between those with or without disease, and expression levels were associated with the genotype of proximal SVAs. This study demonstrates the functional consequences of several SVA elements altering mRNA splicing patterns and expression levels in tissues of the CNS. Full article

(This article belongs to the Special Issue Understanding the Role of Non-coding DNA in Neurodegenerative Disease)

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Review

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15 pages, 1042 KiB

Open AccessReview

The Role of Structural Variants in the Genetic Architecture of Parkinson’s Disease

by Abigail Miano-Burkhardt, Pilar Alvarez Jerez, Kensuke Daida, Sara Bandres Ciga and Kimberley J. Billingsley

Int. J. Mol. Sci. 2024, 25(9), 4801; https://doi.org/10.3390/ijms25094801 - 27 Apr 2024

Viewed by 450

Abstract

Parkinson’s disease (PD) significantly impacts millions of individuals worldwide. Although our understanding of the genetic foundations of PD has advanced, a substantial portion of the genetic variation contributing to disease risk remains unknown. Current PD genetic studies have primarily focused on one form of genetic variation, single nucleotide variants (SNVs), while other important forms of genetic variation, such as structural variants (SVs), are mostly ignored due to the complexity of detecting these variants with traditional sequencing methods. Yet, these forms of genetic variation play crucial roles in gene expression and regulation in the human brain and are causative of numerous neurological disorders, including forms of PD. This review aims to provide a comprehensive overview of our current understanding of the involvement of coding and noncoding SVs in the genetic architecture of PD. Full article

(This article belongs to the Special Issue Understanding the Role of Non-coding DNA in Neurodegenerative Disease)

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