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Genetic Basis of Neurodegenerative Disorders
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Genetic Basis of Neurodegenerative Disorders

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 (15 March 2024) | Viewed by 4289

Special Issue Editor

Dr. Cheong-Meng Chong

E-Mail Website
Guest Editor
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China
Interests: aging; cellular senescence; neurodegenerative diseases; neuropharmacology

Special Issue Information

Dear Colleagues,

Inheritance is one of the main causes of neurodegenerative diseases, such as Alzheimer's disease, Parkinson’s disease, Huntington's disease, multiple sclerosis, and amyotrophic lateral sclerosis. Many pathogenesis-related genes have been identified, most of which show an autosomal dominant mode of inheritance. However, there are still plenty of gene variants as well as genetic networks and mechanisms that remain to be discovered. The genetic basis of neurodegenerative diseases and correlative novel technological advances might shed light on the corresponding genetic diagnoses and therapies.

In this Special Issue, we welcome reviews, original research articles, and new technologies that advance our understanding of the genetic architecture and pathogenic mechanisms underlying neurodegenerative diseases. We are also open to any discoveries in genetic case reports, potential diagnostic biomarkers, and therapeutic approaches.

Dr. Cheong-Meng Chong
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. 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

  • neurodegenerative diseases
  • mutation
  • genetic architecture
  • genetic networks
  • pathogenesis mechanisms

Published Papers (3 papers)

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Research

12 pages, 1057 KiB  
Article
MAPT Locus in Parkinson’s Disease Patients of Ashkenazi Origin: A Stratified Analysis
by Shachar Shani, Mali Gana-Weisz, Anat Bar-Shira, Avner Thaler, Tanya Gurevich, Anat Mirelman, Nir Giladi, Roy N. Alcalay, Orly Goldstein and Avi Orr-Urtreger
Genes 2024, 15(1), 46; https://doi.org/10.3390/genes15010046 - 28 Dec 2023
Viewed by 1215
Abstract
Introduction: MAPT locus is associated with Parkinson’s disease (PD), which is located within a large inversion region of high linkage disequilibrium (LD). We aimed to determine whether the H2-haplotype protective effect and its effect size depends on the GBA1 or LRRK2 risk [...] Read more.
Introduction: MAPT locus is associated with Parkinson’s disease (PD), which is located within a large inversion region of high linkage disequilibrium (LD). We aimed to determine whether the H2-haplotype protective effect and its effect size depends on the GBA1 or LRRK2 risk allele carrier status, and to further characterize genetic alterations that might contribute to its effect. Methods: LD analysis was performed using whole-genome sequencing data of 202 unrelated Ashkenazi Jewish (AJ) PDs. A haplotype-divergent variant was genotyped in a cohort of 1200 consecutively recruited AJ-PDs. The odd ratios were calculated using AJ-non-neuro cases from the gnomAD database as the controls in an un-stratified and a stratified manner according to the mutation carrier status, and the effect on the Age at Motor Symptom Onset (AMSO) was examined. Expression and splicing quantitative trait locus (eQTL and sQTL) analyses were carried out using brain tissues from a database. Results: The H2 haplotype exhibited significant association with PD protection, with a similar effect size in GBA1 carriers, LRRK2-G2019S carriers, and non-carriers (OR = 0.77, 0.69, and 0.82, respectively), and there was no effect on AMSO. The LD interval was narrowed to approximately 1.2 Mb. The H2 haplotype carried potential variants in candidate genes (MAPT and SPPL2C); structural deletions and segmental duplication (KANSL1); and variants affecting gene expression and intron excision ratio in brain tissues (LRRC37A/2). Conclusions: Our results demonstrate that H2 is associated with PD and its protective effect is not influenced by the GBA1/LRRK2 risk allele carrier status. This effect may be genetically complex, resulting from different levels of variations such as missense mutations in relevant genes, structural variations, epigenetic modifications, and RNA expression changes, which may operate independently or in synergy. Full article
(This article belongs to the Special Issue Genetic Basis of Neurodegenerative Disorders)
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16 pages, 1648 KiB  
Article
Comparative Genetic Analysis of the Promoters of the ATG16L1 and ATG5 Genes Associated with Sporadic Parkinson’s Disease
by Ana Gómez-Martín, José M. Fuentes, Joaquín Jordán, María F. Galindo and José Luis Fernández-García
Genes 2023, 14(12), 2171; https://doi.org/10.3390/genes14122171 - 2 Dec 2023
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Abstract
Sporadic Parkinson’s disease, characterised by a decline in dopamine, usually manifests in people over 65 years of age. Although 10% of cases have a genetic (familial) basis, most PD is sporadic. Genome sequencing studies have associated several genetic variants with sporadic PD. Our [...] Read more.
Sporadic Parkinson’s disease, characterised by a decline in dopamine, usually manifests in people over 65 years of age. Although 10% of cases have a genetic (familial) basis, most PD is sporadic. Genome sequencing studies have associated several genetic variants with sporadic PD. Our aim was to analyse the promoter region of the ATG16L1 and ATG5 genes in sporadic PD patients and ethnically matched controls. Genotypes were obtained by using the Sanger method with primers designed by us. The number of haplotypes was estimated with DnaSP software, phylogeny was reconstructed in Network, and genetic divergence was explored with Fst. Seven and two haplotypes were obtained for ATG16L1 and ATG5, respectively. However, only ATG16L1 showed a significant contribution to PD and a significant excess of accumulated mutations that could influence sporadic PD disease. Of a total of seven haplotypes found, only four were unique to patients sharing the T allele (rs77820970). Recent studies using MAPT genes support the notion that the architecture of haplotypes is worthy of being considered genetically risky, as shown in our study, confirming that large-scale assessment in different populations could be relevant to understanding the role of population-specific heterogeneity. Finally, our data suggest that the architecture of certain haplotypes and ethnicity determine the risk of PD, linking haplotype variation and neurodegenerative processes. Full article
(This article belongs to the Special Issue Genetic Basis of Neurodegenerative Disorders)
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15 pages, 6634 KiB  
Article
Identification of Molecular Mechanisms Responsible for the MMP-9-1562C/T Dependent Differential Regulation of Matrix Metalloproteinase-9 Expression in Human Neuron-like Cells
by Sylwia Pabian-Jewuła, Magdalena Ambrożek-Latecka, Aneta Brągiel-Pieczonka, Klaudia Nowicka and Marcin Rylski
Genes 2023, 14(11), 2028; https://doi.org/10.3390/genes14112028 - 31 Oct 2023
Cited by 1 | Viewed by 1391
Abstract
The MMP-9-1562C/T polymorphism exerts an impact on the occurrence and progression of numerous disorders affecting the central nervous system. Using luciferase assays and Q-RT-PCR technique, we have discovered a distinct allele-specific influence of the MMP-9-1562C/T polymorphism on the MMP-9 (Extracellular Matrix Metalloproteinase-9) promoter [...] Read more.
The MMP-9-1562C/T polymorphism exerts an impact on the occurrence and progression of numerous disorders affecting the central nervous system. Using luciferase assays and Q-RT-PCR technique, we have discovered a distinct allele-specific influence of the MMP-9-1562C/T polymorphism on the MMP-9 (Extracellular Matrix Metalloproteinase-9) promoter activity and the expression of MMP-9 mRNA in human neurons derived from SH-SY5Y cells. Subsequently, by employing a pull-down assay paired with mass spectrometry analysis, EMSA (Electromobility Shift Assay), and EMSA supershift techniques, as well as DsiRNA-dependent gene silencing, we have elucidated the mechanism responsible for the allele-specific impact of the MMP-9-1562C/T polymorphism on the transcriptional regulation of the MMP-9 gene. We have discovered that the activity of the MMP-9 promoter and the expression of MMP-9 mRNA in human neurons are regulated in a manner that is specific to the MMP-9-1562C/T allele, with a stronger upregulation being attributed to the C allele. Furthermore, we have demonstrated that the allele-specific action of the MMP-9-1562C/T polymorphism on the neuronal MMP-9 expression is related to HDAC1 (Histone deacetylase 1) and ZNF384 (Zinc Finger Protein 384) transcriptional regulators. We show that HDAC1 and ZNF384 bind to the C and the T alleles differently, forming different regulatory complexes in vitro. Moreover, our data demonstrate that HDAC1 and ZNF384 downregulate MMP-9 gene promoter activity and mRNA expression in human neurons acting mostly via the T allele. Full article
(This article belongs to the Special Issue Genetic Basis of Neurodegenerative Disorders)
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