Genetics and Genomics of Neurodegenerative Diseases

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

Deadline for manuscript submissions: closed (10 August 2021) | Viewed by 24590

Special Issue Editor


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Guest Editor
Department of Rehabilitation Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
Interests: genes; genetics; neurodegeneration; neuroregeneration; neural repair
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Special Issue Information

Dear Colleagues,

Genetic factors are essential to the pathogenic mechanism in neurodegenerative disease, as genetic causes or as modifiers of susceptibility to sporadic diseases. The identification of disease-causing genes has led to advances in the treatment modifying the target genes and the disease phenotypes. Recent research has been expanding our understanding of the genetics and genomics as a personalized medicine in neurodegenerative diseases such as Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, as well as Alzheimer’s disease or other neurodegenerative dementia. Articles submitted to this Special Issue should include basic and clinical studies, translational research, and clinical trials which should provide insights into the diagnosis, pathophysiology, and treatment of neurodegenerative diseases as mentioned above. We would like to invite you to submit your research work within the scope of the Special Issue, including not only bioinformatic gene analysis but also genetic and genomic changes following various treatments such as pharmacologic treatment, physical exercise, environmental enrichment, magnetic stimulation, electrical stimulation and so on for publication.

Dr. Sung-Rae Cho
Guest Editor

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Keywords

  • Genes
  • Genetics
  • Genomics
  • Bioinformatics
  • Neurodegenerative Disease
  • Parkinson’s disease
  • Huntington’s disease
  • Amyotrophic lateral sclerosis
  • Alzheimer’s disease
  • Dementia

Published Papers (7 papers)

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Research

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16 pages, 9795 KiB  
Article
Association and Gene–Gene Interactions Study of Late-Onset Alzheimer’s Disease in the Russian Population
by Anna Bocharova, Kseniya Vagaitseva, Andrey Marusin, Natalia Zhukova, Irina Zhukova, Larisa Minaycheva, Oksana Makeeva and Vadim Stepanov
Genes 2021, 12(10), 1647; https://doi.org/10.3390/genes12101647 - 19 Oct 2021
Cited by 5 | Viewed by 2715
Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder, and represents the most common cause of dementia. In this study, we performed several different analyses to detect loci involved in development of the late onset AD in the Russian population. DNA samples from 472 unrelated [...] Read more.
Alzheimer’s disease (AD) is a neurodegenerative disorder, and represents the most common cause of dementia. In this study, we performed several different analyses to detect loci involved in development of the late onset AD in the Russian population. DNA samples from 472 unrelated subjects were genotyped for 63 SNPs using iPLEX Assay and real-time PCR. We identified five genetic loci that were significantly associated with LOAD risk for the Russian population (TOMM40 rs2075650, APOE rs429358 and rs769449, NECTIN rs6857, APOE ε4). The results of the analysis based on comparison of the haplotype frequencies showed two risk haplotypes and one protective haplotype. The GMDR analysis demonstrated three significant models as a result: a one-factor, a two-factor and a three-factor model. A protein–protein interaction network with three subnetworks was formed for the 24 proteins. Eight proteins with a large number of interactions are identified: APOE, SORL1, APOC1, CD33, CLU, TOMM40, CNTNAP2 and CACNA1C. The present study confirms the importance of the APOE-TOMM40 locus as the main risk locus of development and progress of LOAD in the Russian population. Association analysis and bioinformatics approaches detected interactions both at the association level of single SNPs and at the level of genes and proteins. Full article
(This article belongs to the Special Issue Genetics and Genomics of Neurodegenerative Diseases)
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14 pages, 2659 KiB  
Article
Reelin Alleviates Mesenchymal Stem Cell Senescence and Reduces Pathological α-Synuclein Expression in an In Vitro Model of Parkinson’s Disease
by Eunju Cho, Joonsang Park, Kyungri Kim, Min-Gi Kim and Sung-Rae Cho
Genes 2021, 12(7), 1066; https://doi.org/10.3390/genes12071066 - 13 Jul 2021
Cited by 4 | Viewed by 2893
Abstract
Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. The mechanisms underlying PD remain to be fully elucidated, and research into treatments for this condition is ongoing. Recent advances in genetic research have shed light on the mechanisms underlying PD. In [...] Read more.
Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. The mechanisms underlying PD remain to be fully elucidated, and research into treatments for this condition is ongoing. Recent advances in genetic research have shed light on the mechanisms underlying PD. In this study, we used PD and control mesenchymal stem cells (MSCs) obtained from adipose tissues to confirm the differences between groups at the cellular and molecular levels. The results revealed that in PD MSCs, cell viability was clearly lower, and the rate of cell senescence was higher compared to the controls. Next, to compare the gene expression in PD and control cells, transcriptome analysis was performed. Genes in pathways, including extracellular matrix (ECM) receptor interaction, P53 signaling, and focal adhesion, were down-regulated in PD. Among genes related to ECM receptor interaction, RELN gene expression was markedly decreased in PD cells; however, after being treated with recombinant Reelin protein, a significant increase in cell viability and a decrease in α-Synuclein aggregation and cell senescence were observed. In conclusion, Reelin affects PD by positively influencing the cell characteristics. Our findings will facilitate research into new treatments for PD. Full article
(This article belongs to the Special Issue Genetics and Genomics of Neurodegenerative Diseases)
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8 pages, 698 KiB  
Article
Causal Association between Periodontitis and Parkinson’s Disease: A Bidirectional Mendelian Randomization Study
by João Botelho, Vanessa Machado, José João Mendes and Paulo Mascarenhas
Genes 2021, 12(5), 772; https://doi.org/10.3390/genes12050772 - 19 May 2021
Cited by 9 | Viewed by 4304
Abstract
The latest evidence revealed a possible association between periodontitis and Parkinson’s disease (PD). We explored the causal relationship of this bidirectional association through two-sample Mendelian randomization (MR) in European ancestry populations. To this end, we used openly accessible data of genome-wide association studies [...] Read more.
The latest evidence revealed a possible association between periodontitis and Parkinson’s disease (PD). We explored the causal relationship of this bidirectional association through two-sample Mendelian randomization (MR) in European ancestry populations. To this end, we used openly accessible data of genome-wide association studies (GWAS) on periodontitis and PD. As instrumental variables for periodontitis, seventeen single-nucleotide polymorphisms (SNPs) from a GWAS of periodontitis (1817 periodontitis cases vs. 2215 controls) and eight non-overlapping SNPs of periodontitis from an additional GWAS for validation purposes. Instrumental variables to explore for the reverse causation included forty-five SNPs from a GWAS of PD (20,184 cases and 397,324 controls). Multiple approaches of MR were carried-out. There was no evidence of genetic liability of periodontitis being associated with a higher risk of PD (B = −0.0003, Standard Error [SE] 0.0003, p = 0.26). The eight independent SNPs (B = −0.0000, SE 0.0001, p = 0.99) validated this outcome. We also found no association of genetically primed PD towards periodontitis (B = −0.0001, SE 0.0001, p = 0.19). These MR study findings do not support a bidirectional causal genetic liability between periodontitis and PD. Further GWAS studies are needed to confirm the consistency of these results. Full article
(This article belongs to the Special Issue Genetics and Genomics of Neurodegenerative Diseases)
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19 pages, 5312 KiB  
Article
In Vivo Expression of Reprogramming Factor OCT4 Ameliorates Myelination Deficits and Induces Striatal Neuroprotection in Huntington’s Disease
by Ji-Hea Yu, Bae-Geun Nam, Min-Gi Kim, Soonil Pyo, Jung-Hwa Seo and Sung-Rae Cho
Genes 2021, 12(5), 712; https://doi.org/10.3390/genes12050712 - 10 May 2021
Cited by 3 | Viewed by 2663
Abstract
White matter atrophy has been shown to precede the massive loss of striatal GABAergic neurons in Huntington’s disease (HD). This study investigated the effects of in vivo expression of reprogramming factor octamer-binding transcription factor 4 (OCT4) on neural stem cell (NSC) niche activation [...] Read more.
White matter atrophy has been shown to precede the massive loss of striatal GABAergic neurons in Huntington’s disease (HD). This study investigated the effects of in vivo expression of reprogramming factor octamer-binding transcription factor 4 (OCT4) on neural stem cell (NSC) niche activation in the subventricular zone (SVZ) and induction of cell fate specific to the microenvironment of HD. R6/2 mice randomly received adeno-associated virus 9 (AAV9)-OCT4, AAV9-Null, or phosphate-buffered saline into both lateral ventricles at 4 weeks of age. The AAV9-OCT4 group displayed significantly improved behavioral performance compared to the control groups. Following AAV9-OCT4 treatment, the number of newly generated NSCs and oligodendrocyte progenitor cells (OPCs) significantly increased in the SVZ, and the expression of OPC-related genes and glial cell-derived neurotrophic factor (GDNF) significantly increased. Further, amelioration of myelination deficits in the corpus callosum was observed through electron microscopy and magnetic resonance imaging, and striatal DARPP32+ GABAergic neurons significantly increased in the AAV9-OCT4 group. These results suggest that in situ expression of the reprogramming factor OCT4 in the SVZ induces OPC proliferation, thereby attenuating myelination deficits. Particularly, GDNF released by OPCs seems to induce striatal neuroprotection in HD, which explains the behavioral improvement in R6/2 mice overexpressing OCT4. Full article
(This article belongs to the Special Issue Genetics and Genomics of Neurodegenerative Diseases)
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15 pages, 20492 KiB  
Article
Reduced Interaction of Aggregated α-Synuclein and VAMP2 by Environmental Enrichment Alleviates Hyperactivity and Anxiety in a Model of Parkinson’s Disease
by Kyungri Kim, Soohyun Wi, Jung Hwa Seo, Soonil Pyo and Sung-Rae Cho
Genes 2021, 12(3), 392; https://doi.org/10.3390/genes12030392 - 10 Mar 2021
Cited by 12 | Viewed by 3208
Abstract
Parkinson’s disease (PD) is a prevalent motor disease caused by the accumulation of mutated α-synuclein (α-Syn); however, its early stages are also characterized by non-motor symptoms, such as olfactory loss, cognitive decline, depression, and anxiety. The therapeutic effects of environmental enrichment (EE) on [...] Read more.
Parkinson’s disease (PD) is a prevalent motor disease caused by the accumulation of mutated α-synuclein (α-Syn); however, its early stages are also characterized by non-motor symptoms, such as olfactory loss, cognitive decline, depression, and anxiety. The therapeutic effects of environmental enrichment (EE) on motor recovery have been reported, but its effects on non-motor symptoms remain unclear. Herein, we reveal the beneficial effects of EE on PD-related non-motor symptoms and changes in synaptic plasticity in the nucleus accumbens. To investigate its therapeutic effects in the early phase of PD, we randomly assigned eight-month-old mice overexpressing human A53T (hA53T) α-Syn to either the EE or standard condition groups for two months. Next, we performed behavioral tests and biochemical and histological analyses at 10 months of age. EE significantly alleviated locomotor hyperactivity and anxiety during the early stages of PD. It normalized the levels of tyrosine hydroxylase, phosphorylated and oligomeric α-Syn, and soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex-forming proteins, including synaptosomal-associated protein, 25 kDa, syntaxin1, and vesicle-associated membrane protein 2 (VAMP2). Moreover, the interactions between VAMP2 and pSer129 α-Syn were markedly reduced following EE. The restoration of synaptic vesicle transportation status may underlie the neuroprotective effects of EE in hA53T α-Syn mice. Full article
(This article belongs to the Special Issue Genetics and Genomics of Neurodegenerative Diseases)
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15 pages, 1570 KiB  
Article
Network Protein Interaction in Parkinson’s Disease and Periodontitis Interplay: A Preliminary Bioinformatic Analysis
by João Botelho, Paulo Mascarenhas, José João Mendes and Vanessa Machado
Genes 2020, 11(11), 1385; https://doi.org/10.3390/genes11111385 - 23 Nov 2020
Cited by 11 | Viewed by 3798
Abstract
Recent studies supported a clinical association between Parkinson’s disease (PD) and periodontitis. Hence, investigating possible interactions between proteins associated to these two conditions is of interest. In this study, we conducted a protein–protein network interaction analysis with recognized genes encoding proteins with variants [...] Read more.
Recent studies supported a clinical association between Parkinson’s disease (PD) and periodontitis. Hence, investigating possible interactions between proteins associated to these two conditions is of interest. In this study, we conducted a protein–protein network interaction analysis with recognized genes encoding proteins with variants strongly associated with PD and periodontitis. Genes of interest were collected via the Genome-Wide Association Studies (GWAS) database. Then, we conducted a protein interaction analysis, using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database, with a highest confidence cutoff of 0.9 and sensitivity analysis with confidence cutoff of 0.7. Our protein network casts a comprehensive analysis of potential protein–protein interactions between PD and periodontitis. This analysis may underpin valuable information for new candidate molecular mechanisms between PD and periodontitis and may serve new potential targets for research purposes. These results should be carefully interpreted, giving the limitations of this approach. Full article
(This article belongs to the Special Issue Genetics and Genomics of Neurodegenerative Diseases)
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Review

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19 pages, 2086 KiB  
Review
LRRK2 at the Crossroad of Aging and Parkinson’s Disease
by Eun-Mi Hur and Byoung Dae Lee
Genes 2021, 12(4), 505; https://doi.org/10.3390/genes12040505 - 29 Mar 2021
Cited by 15 | Viewed by 3849
Abstract
Parkinson’s disease (PD) is a heterogeneous neurodegenerative disease characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta and the widespread occurrence of proteinaceous inclusions known as Lewy bodies and Lewy neurites. The etiology of PD is still far [...] Read more.
Parkinson’s disease (PD) is a heterogeneous neurodegenerative disease characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta and the widespread occurrence of proteinaceous inclusions known as Lewy bodies and Lewy neurites. The etiology of PD is still far from clear, but aging has been considered as the highest risk factor influencing the clinical presentations and the progression of PD. Accumulating evidence suggests that aging and PD induce common changes in multiple cellular functions, including redox imbalance, mitochondria dysfunction, and impaired proteostasis. Age-dependent deteriorations in cellular dysfunction may predispose individuals to PD, and cellular damages caused by genetic and/or environmental risk factors of PD may be exaggerated by aging. Mutations in the LRRK2 gene cause late-onset, autosomal dominant PD and comprise the most common genetic causes of both familial and sporadic PD. LRRK2-linked PD patients show clinical and pathological features indistinguishable from idiopathic PD patients. Here, we review cellular dysfunctions shared by aging and PD-associated LRRK2 mutations and discuss how the interplay between the two might play a role in PD pathologies. Full article
(This article belongs to the Special Issue Genetics and Genomics of Neurodegenerative Diseases)
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