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Genetics of Neurodegenerative Diseases 2.0
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Genetics of Neurodegenerative Diseases 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (30 November 2020) | Viewed by 61797

Special Issue Editors

Dr. Cristoforo Comi

E-Mail Website
Guest Editor
Department of Translational Medicine, Section of Neurology, University of Piemonte Orientale, 28100 Novara, Italy
Interests: neurodegenerative diseases including Parkinson\'s disease, Huntington disease, other movement disorders, Alzheimer\'s disease; neuroimmune diseases including: multiple sclerosis, inflammatory neuropathies, myasthenia gravis
Special Issues, Collections and Topics in MDPI journals
Dr. Alessio Di Fonzo

E-Mail Website
Co-Guest Editor
Neurology Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, 20122 Milan, Italy
Interests: Parkinson’s Disease; Neurogenetics; Genetic Dystonia; Genetic Ataxia
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Genetic susceptibility to neurodegenerative disease has been the object of a large body of research in the last twenty years. Important results both in monogenic heritable diseases and in complex, sporadic disorders have been reached. By contrast, only a few studies have addressed the role of disease-modifying genes and/or pharmacogenomic aspects. This might be related to the difficulty in collecting data on disease evolution and response to treatment compared to recording disease development. To fill this gap, large collaborative studies aimed at tracking disease evolution are ongoing, and results are likely to provide insightful information on the determinants of progression.

Variations in glucocerebrosidase (GBA), leucine-rich repeat kinase 2 (LRRK2), and alpha-synuclein (SNCA) genes, just to name a few, have already been associated to specific features of Parkinson’s disease (PD), and an effort was recently made to classify PD subtypes in order to better clarify genotype/phenotype correlations. Furthermore, single nucleotide polymorphisms (SNPs) in receptor genes have been associated to development of PD complications. Furthermore, research performed in Alzheimer’s disease (AD) showed that variations in serine racemase (SRR) or in 3-Hydroxy-3-Methylglutaryl-CoA reductase (HMGCR) genes can influence disease progression.

Taken altogether, these findings depict a landscape in which individual genetic profiling will be increasingly relevant in a clinical context, with implications for patient care in line with the proposed ideal of personalized medicine.

On this background, the aim of this Special Issue of the International Journal of Molecular Sciences is to attract high-quality studies covering the relationship between gene variations and clinical features of neurodegenerative diseases. Contributors are encouraged to submit articles describing novel results, models, viewpoints, perspectives, and/or methodological innovations. We will strive to ensure that the articles of the Special Issue collectively present a cohesive picture of the state-of-the-art in the field and help to advance our understanding and management of neurodegenerative diseases.

The topics we wish to cover include but are not limited to:

  • Genetic determinants of faster neurodegenerative disease evolution;
  • Genetic predisposition to motor and nonmotor complications in PD;
  • The role of genetic background in treatment response in neurodegenerative disease;
  • The genetic background of Parkinson’s disease dementia and Lewy body dementia;
  • Genotype/phenotype correlations in atypical Parkinsonian syndromes.

Dr. Cristoforo Comi
Dr. Alessio Di Fonzo
Guest Editors

Manuscript Submission Information

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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.

Published Papers (15 papers)

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Research

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18 pages, 3479 KiB  
Article
C9ORF72 Repeat Expansion Affects the Proteome of Primary Skin Fibroblasts in ALS
by Marta Lualdi, Adeena Shafique, Edoardo Pedrini, Luisa Pieroni, Viviana Greco, Massimo Castagnola, Giorgia Cucina, Lucia Corrado, Alice Di Pierro, Fabiola De Marchi, Lara Camillo, Claudia Colombrita, Marianna D’Anca, Tiziana Alberio, Sandra D’Alfonso and Mauro Fasano
Int. J. Mol. Sci. 2021, 22(19), 10385; https://doi.org/10.3390/ijms221910385 - 27 Sep 2021
Cited by 5 | Viewed by 2864
Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of the corticospinal motor neurons, which ultimately leads to death. The repeat expansion in chromosome 9 open reading frame 72 (C9ORF72) represents the most common genetic cause of ALS [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of the corticospinal motor neurons, which ultimately leads to death. The repeat expansion in chromosome 9 open reading frame 72 (C9ORF72) represents the most common genetic cause of ALS and it is also involved in the pathogenesis of other neurodegenerative disorders. To offer insights into C9ORF72-mediated pathogenesis, we quantitatively analyzed the proteome of patient-derived primary skin fibroblasts from ALS patients carrying the C9ORF72 mutation compared with ALS patients who tested negative for it. Differentially expressed proteins were identified, used to generate a protein-protein interaction network and subjected to a functional enrichment analysis to unveil altered molecular pathways. ALS patients were also compared with patients affected by frontotemporal dementia carrying the C9ORF72 repeat expansion. As a result, we demonstrated that the molecular pathways mainly altered in fibroblasts (e.g., protein homeostasis) mirror the alterations observed in C9ORF72-mutated neurons. Moreover, we highlighted novel molecular pathways (nuclear and mitochondrial transports, vesicle trafficking, mitochondrial bioenergetics, glucose metabolism, ER-phagosome crosstalk and Slit/Robo signaling pathway) which might be further investigated as C9ORF72-specific pathogenetic mechanisms. Data are available via ProteomeXchange with the identifier PXD023866. Full article
(This article belongs to the Special Issue Genetics of Neurodegenerative Diseases 2.0)
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28 pages, 5118 KiB  
Article
DCTN1 Binds to TDP-43 and Regulates TDP-43 Aggregation
by Manami Deshimaru, Mariko Kinoshita-Kawada, Kaori Kubota, Takuya Watanabe, Yasuyoshi Tanaka, Saito Hirano, Fumiyoshi Ishidate, Masaki Hiramoto, Mitsuru Ishikawa, Yoshinari Uehara, Hideyuki Okano, Shinichi Hirose, Shinsuke Fujioka, Katsunori Iwasaki, Junichi Yuasa-Kawada, Takayasu Mishima and Yoshio Tsuboi
Int. J. Mol. Sci. 2021, 22(8), 3985; https://doi.org/10.3390/ijms22083985 - 13 Apr 2021
Cited by 19 | Viewed by 6029
Abstract
A common pathological hallmark of several neurodegenerative diseases, including amyotrophic lateral sclerosis, is cytoplasmic mislocalization and aggregation of nuclear RNA-binding protein TDP-43. Perry disease, which displays inherited atypical parkinsonism, is a type of TDP-43 proteinopathy. The causative gene DCTN1 encodes the largest subunit [...] Read more.
A common pathological hallmark of several neurodegenerative diseases, including amyotrophic lateral sclerosis, is cytoplasmic mislocalization and aggregation of nuclear RNA-binding protein TDP-43. Perry disease, which displays inherited atypical parkinsonism, is a type of TDP-43 proteinopathy. The causative gene DCTN1 encodes the largest subunit of the dynactin complex. Dynactin associates with the microtubule-based motor cytoplasmic dynein and is required for dynein-mediated long-distance retrograde transport. Perry disease-linked missense mutations (e.g., p.G71A) reside within the CAP-Gly domain and impair the microtubule-binding abilities of DCTN1. However, molecular mechanisms by which such DCTN1 mutations cause TDP-43 proteinopathy remain unclear. We found that DCTN1 bound to TDP-43. Biochemical analysis using a panel of truncated mutants revealed that the DCTN1 CAP-Gly-basic supradomain, dynactin domain, and C-terminal region interacted with TDP-43, preferentially through its C-terminal region. Remarkably, the p.G71A mutation affected the TDP-43-interacting ability of DCTN1. Overexpression of DCTN1G71A, the dynactin-domain fragment, or C-terminal fragment, but not the CAP-Gly-basic fragment, induced cytoplasmic mislocalization and aggregation of TDP-43, suggesting functional modularity among TDP-43-interacting domains of DCTN1. We thus identified DCTN1 as a new player in TDP-43 cytoplasmic-nuclear transport, and showed that dysregulation of DCTN1-TDP-43 interactions triggers mislocalization and aggregation of TDP-43, thus providing insights into the pathological mechanisms of Perry disease and other TDP-43 proteinopathies. Full article
(This article belongs to the Special Issue Genetics of Neurodegenerative Diseases 2.0)
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16 pages, 15254 KiB  
Article
Alzheimer’s, Parkinson’s Disease and Amyotrophic Lateral Sclerosis Gene Expression Patterns Divergence Reveals Different Grade of RNA Metabolism Involvement
by Maria Garofalo, Cecilia Pandini, Matteo Bordoni, Orietta Pansarasa, Federica Rey, Alfredo Costa, Brigida Minafra, Luca Diamanti, Susanna Zucca, Stephana Carelli, Cristina Cereda and Stella Gagliardi
Int. J. Mol. Sci. 2020, 21(24), 9500; https://doi.org/10.3390/ijms21249500 - 14 Dec 2020
Cited by 22 | Viewed by 4077
Abstract
Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders characterized by a progressive degeneration of the central or peripheral nervous systems. A central role of the RNA metabolism has emerged in these diseases, concerning mRNAs processing and non-coding [...] Read more.
Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS) are neurodegenerative disorders characterized by a progressive degeneration of the central or peripheral nervous systems. A central role of the RNA metabolism has emerged in these diseases, concerning mRNAs processing and non-coding RNAs biogenesis. We aimed to identify possible common grounds or differences in the dysregulated pathways of AD, PD, and ALS. To do so, we performed RNA-seq analysis to investigate the deregulation of both coding and long non-coding RNAs (lncRNAs) in ALS, AD, and PD patients and controls (CTRL) in peripheral blood mononuclear cells (PBMCs). A total of 293 differentially expressed (DE) lncRNAs and 87 mRNAs were found in ALS patients. In AD patients a total of 23 DE genes emerged, 19 protein coding genes and four lncRNAs. Through Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses, we found common affected pathways and biological processes in ALS and AD. In PD patients only five genes were found to be DE. Our data brought to light the importance of lncRNAs and mRNAs regulation in three principal neurodegenerative disorders, offering starting points for new investigations on deregulated pathogenic mechanisms. Full article
(This article belongs to the Special Issue Genetics of Neurodegenerative Diseases 2.0)
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15 pages, 2502 KiB  
Article
Sonic Hedgehog-Gli1 Signaling and Cellular Retinoic Acid Binding Protein 1 Gene Regulation in Motor Neuron Differentiation and Diseases
by Yu-Lung Lin, Yi-Wei Lin, Jennifer Nhieu, Xiaoyin Zhang and Li-Na Wei
Int. J. Mol. Sci. 2020, 21(11), 4125; https://doi.org/10.3390/ijms21114125 - 09 Jun 2020
Cited by 16 | Viewed by 4000
Abstract
Cellular retinoic acid-binding protein 1 (CRABP1) is highly expressed in motor neurons. Degenerated motor neuron-like MN1 cells are engineered by introducing SODG93A or AR-65Q to model degenerated amyotrophic lateral sclerosis (ALS) or spinal bulbar muscular atrophy neurons. Retinoic acid (RA)/sonic hedgehog (Shh)-induced [...] Read more.
Cellular retinoic acid-binding protein 1 (CRABP1) is highly expressed in motor neurons. Degenerated motor neuron-like MN1 cells are engineered by introducing SODG93A or AR-65Q to model degenerated amyotrophic lateral sclerosis (ALS) or spinal bulbar muscular atrophy neurons. Retinoic acid (RA)/sonic hedgehog (Shh)-induced embryonic stem cells differentiation into motor neurons are employed to study up-regulation of Crabp1 by Shh. In SODG93A or AR-65Q MN1 neurons, CRABP1 level is reduced, revealing a correlation of motor neuron degeneration with Crabp1 down-regulation. Up-regulation of Crabp1 by Shh is mediated by glioma-associated oncogene homolog 1 (Gli1) that binds the Gli target sequence in Crabp1′s neuron-specific regulatory region upstream of minimal promoter. Gli1 binding triggers chromatin juxtaposition with minimal promoter, activating transcription. Motor neuron differentiation and Crabp1 up-regulation are both inhibited by blunting Shh with Gli inhibitor GANT61. Expression data mining of ALS and spinal muscular atrophy (SMA) motor neurons shows reduced CRABP1, coincided with reduction in Shh-Gli1 signaling components. This study reports motor neuron degeneration correlated with down-regulation in Crabp1 and Shh-Gli signaling. Shh-Gli up-regulation of Crabp1 involves specific chromatin remodeling. The physiological and pathological implication of this regulatory pathway in motor neuron degeneration is supported by gene expression data of ALS and SMA patients. Full article
(This article belongs to the Special Issue Genetics of Neurodegenerative Diseases 2.0)
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19 pages, 4447 KiB  
Article
miR-129-5p and miR-130a-3p Regulate VEGFR-2 Expression in Sensory and Motor Neurons during Development
by Kevin Glaesel, Caroline May, Katrin Marcus, Veronika Matschke, Carsten Theiss and Verena Theis
Int. J. Mol. Sci. 2020, 21(11), 3839; https://doi.org/10.3390/ijms21113839 - 28 May 2020
Cited by 16 | Viewed by 3075
Abstract
The wide-ranging influence of vascular endothelial growth factor (VEGF) within the central (CNS) and peripheral nervous system (PNS), for example through effects on axonal growth or neuronal cell survival, is mainly mediated by VEGF receptor 2 (VEGFR-2). However, the regulation of VEGFR-2 expression [...] Read more.
The wide-ranging influence of vascular endothelial growth factor (VEGF) within the central (CNS) and peripheral nervous system (PNS), for example through effects on axonal growth or neuronal cell survival, is mainly mediated by VEGF receptor 2 (VEGFR-2). However, the regulation of VEGFR-2 expression during development is not yet well understood. As microRNAs are considered to be key players during neuronal maturation and regenerative processes, we identified the two microRNAs (miRNAs)—miR-129-5p and miR-130a-3p—that may have an impact on VEGFR-2 expression in young and mature sensory and lower motor neurons. The expression level of VEGFR-2 was analyzed by using in situ hybridization, RT-qPCR, Western blot, and immunohistochemistry in developing rats. microRNAs were validated within the spinal cord and dorsal root ganglia. To unveil the molecular impact of our candidate microRNAs, dissociated cell cultures of sensory and lower motor neurons were transfected with mimics and inhibitors. We depicted age-dependent VEGFR-2 expression in sensory and lower motor neurons. In detail, in lower motor neurons, VEGFR-2 expression was significantly reduced during maturation, in conjunction with an increased level of miR-129-5p. In sensory dorsal root ganglia, VEGFR-2 expression increased during maturation and was accompanied by an overexpression of miR-130a-3p. In a second step, the functional significance of these microRNAs with respect to VEGFR-2 expression was proven. Whereas miR-129-5p seems to decrease VEGFR-2 expression in a direct manner in the CNS, miR-130a-3p might indirectly control VEGFR-2 expression in the PNS. A detailed understanding of genetic VEGFR-2 expression control might promote new strategies for the treatment of severe neurological diseases like ischemia or peripheral nerve injury. Full article
(This article belongs to the Special Issue Genetics of Neurodegenerative Diseases 2.0)
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17 pages, 1773 KiB  
Article
C-Fiber Loss as a Possible Cause of Neuropathic Pain in Schwannomatosis
by Said C. Farschtschi, Tina Mainka, Markus Glatzel, Anna-Lena Hannekum, Michael Hauck, Mathias Gelderblom, Christian Hagel, Reinhard E. Friedrich, Martin U. Schuhmann, Alexander Schulz, Helen Morrison, Hildegard Kehrer-Sawatzki, Jan Luhmann, Christian Gerloff, Martin Bendszus, Philipp Bäumer and Victor-Felix Mautner
Int. J. Mol. Sci. 2020, 21(10), 3569; https://doi.org/10.3390/ijms21103569 - 18 May 2020
Cited by 6 | Viewed by 2836
Abstract
Schwannomatosis is the third form of neurofibromatosis and characterized by the occurrence of multiple schwannomas. The most prominent symptom is chronic pain. We aimed to test whether pain in schwannomatosis might be caused by small-fiber neuropathy. Twenty patients with schwannomatosis underwent neurological examination [...] Read more.
Schwannomatosis is the third form of neurofibromatosis and characterized by the occurrence of multiple schwannomas. The most prominent symptom is chronic pain. We aimed to test whether pain in schwannomatosis might be caused by small-fiber neuropathy. Twenty patients with schwannomatosis underwent neurological examination and nerve conduction studies. Levels of pain perception as well as anxiety and depression were assessed by established questionnaires. Quantitative sensory testing (QST) and laser-evoked potentials (LEP) were performed on patients and controls. Whole-body magnetic resonance imaging (wbMRI) and magnetic resonance neurography (MRN) were performed to quantify tumors and fascicular nerve lesions; skin biopsies were performed to determine intra-epidermal nerve fiber density (IENFD). All patients suffered from chronic pain without further neurological deficits. The questionnaires indicated neuropathic symptoms with significant impact on quality of life. Peripheral nerve tumors were detected in all patients by wbMRI. MRN showed additional multiple fascicular nerve lesions in 16/18 patients. LEP showed significant faster latencies compared to normal controls. Finally, IENFD was significantly reduced in 13/14 patients. Our study therefore indicates the presence of small-fiber neuropathy, predominantly of unmyelinated C-fibers. Fascicular nerve lesions are characteristic disease features that are associated with faster LEP latencies and decreased IENFD. Together these methods may facilitate differential diagnosis of schwannomatosis. Full article
(This article belongs to the Special Issue Genetics of Neurodegenerative Diseases 2.0)
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Review

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22 pages, 397 KiB  
Review
Detection of Morphological Abnormalities in Schizophrenia: An Important Step to Identify Associated Genetic Disorders or Etiologic Subtypes
by Anne-Clémence Priol, Laure Denis, Gaella Boulanger, Mathieu Thépaut, Marie-Maude Geoffray and Sylvie Tordjman
Int. J. Mol. Sci. 2021, 22(17), 9464; https://doi.org/10.3390/ijms22179464 - 31 Aug 2021
Cited by 6 | Viewed by 3318
Abstract
Current research suggests that alterations in neurodevelopmental processes, involving gene X environment interactions during key stages of brain development (prenatal period and adolescence), are a major risk for schizophrenia. First, epidemiological studies supporting a genetic contribution to schizophrenia are presented in this article, [...] Read more.
Current research suggests that alterations in neurodevelopmental processes, involving gene X environment interactions during key stages of brain development (prenatal period and adolescence), are a major risk for schizophrenia. First, epidemiological studies supporting a genetic contribution to schizophrenia are presented in this article, including family, twin, and adoption studies. Then, an extensive literature review on genetic disorders associated with schizophrenia is reviewed. These epidemiological findings and clinical observations led researchers to conduct studies on genetic associations in schizophrenia, and more specifically on genomics (CNV: copy-number variant, and SNP: single nucleotide polymorphism). The main structural (CNV) and sequence (SNP) variants found in individuals with schizophrenia are reported here. Evidence of genetic contributions to schizophrenia and current knowledge on genetic syndromes associated with this psychiatric disorder highlight the importance of a clinical genetic examination to detect minor physical anomalies in individuals with ultra-high risk of schizophrenia. Several dysmorphic features have been described in schizophrenia, especially in early onset schizophrenia, and can be viewed as neurodevelopmental markers of vulnerability. Early detection of individuals with neurodevelopmental abnormalities is a fundamental issue to develop prevention and diagnostic strategies, therapeutic intervention and follow-up, and to ascertain better the underlying mechanisms involved in the pathophysiology of schizophrenia. Full article
(This article belongs to the Special Issue Genetics of Neurodegenerative Diseases 2.0)
30 pages, 2647 KiB  
Review
Non-Rodent Genetic Animal Models for Studying Tauopathy: Review of Drosophila, Zebrafish, and C. elegans Models
by Hoi-Khoanh Giong, Manivannan Subramanian, Kweon Yu and Jeong-Soo Lee
Int. J. Mol. Sci. 2021, 22(16), 8465; https://doi.org/10.3390/ijms22168465 - 06 Aug 2021
Cited by 12 | Viewed by 3502
Abstract
Tauopathy refers to a group of progressive neurodegenerative diseases, including frontotemporal lobar degeneration and Alzheimer’s disease, which correlate with the malfunction of microtubule-associated protein Tau (MAPT) due to abnormal hyperphosphorylation, leading to the formation of intracellular aggregates in the brain. Despite extensive efforts [...] Read more.
Tauopathy refers to a group of progressive neurodegenerative diseases, including frontotemporal lobar degeneration and Alzheimer’s disease, which correlate with the malfunction of microtubule-associated protein Tau (MAPT) due to abnormal hyperphosphorylation, leading to the formation of intracellular aggregates in the brain. Despite extensive efforts to understand tauopathy and develop an efficient therapy, our knowledge is still far from complete. To find a solution for this group of devastating diseases, several animal models that mimic diverse disease phenotypes of tauopathy have been developed. Rodents are the dominating tauopathy models because of their similarity to humans and established disease lines, as well as experimental approaches. However, powerful genetic animal models using Drosophila, zebrafish, and C. elegans have also been developed for modeling tauopathy and have contributed to understanding the pathophysiology of tauopathy. The success of these models stems from the short lifespans, versatile genetic tools, real-time in-vivo imaging, low maintenance costs, and the capability for high-throughput screening. In this review, we summarize the main findings on mechanisms of tauopathy and discuss the current tauopathy models of these non-rodent genetic animals, highlighting their key advantages and limitations in tauopathy research. Full article
(This article belongs to the Special Issue Genetics of Neurodegenerative Diseases 2.0)
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18 pages, 1154 KiB  
Review
MicroRNAs, Parkinson’s Disease, and Diabetes Mellitus
by Hsiuying Wang
Int. J. Mol. Sci. 2021, 22(6), 2953; https://doi.org/10.3390/ijms22062953 - 14 Mar 2021
Cited by 14 | Viewed by 3554
Abstract
Parkinson’s disease (PD) is a neurodegenerative disorder that affects 1% of the population over the age of 60. Diabetes Mellitus (DM) is a metabolic disorder that affects approximately 25% of adults over the age of 60. Recent studies showed that DM increases the [...] Read more.
Parkinson’s disease (PD) is a neurodegenerative disorder that affects 1% of the population over the age of 60. Diabetes Mellitus (DM) is a metabolic disorder that affects approximately 25% of adults over the age of 60. Recent studies showed that DM increases the risk of developing PD. The link between DM and PD has been discussed in the literature in relation to different mechanisms including mitochondrial dysfunction, oxidative stress, and protein aggregation. In this paper, we review the common microRNA (miRNA) biomarkers of both diseases. miRNAs play an important role in cell differentiation, development, the regulation of the cell cycle, and apoptosis. They are also involved in the pathology of many diseases. miRNAs can mediate the insulin pathway and glucose absorption. miRNAs can also regulate PD-related genes. Therefore, exploring the common miRNA biomarkers of both PD and DM can shed a light on how these two diseases are correlated, and targeting miRNAs is a potential therapeutic opportunity for both diseases. Full article
(This article belongs to the Special Issue Genetics of Neurodegenerative Diseases 2.0)
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12 pages, 494 KiB  
Review
The NFκB Antagonist CDGSH Iron-Sulfur Domain 2 Is a Promising Target for the Treatment of Neurodegenerative Diseases
by Woon-Man Kung and Muh-Shi Lin
Int. J. Mol. Sci. 2021, 22(2), 934; https://doi.org/10.3390/ijms22020934 - 19 Jan 2021
Cited by 8 | Viewed by 1966
Abstract
Proinflammatory response and mitochondrial dysfunction are related to the pathogenesis of neurodegenerative diseases (NDs). Nuclear factor κB (NFκB) activation has been shown to exaggerate proinflammation and mitochondrial dysfunction, which underlies NDs. CDGSH iron-sulfur domain 2 (CISD2) has been shown to be associated with [...] Read more.
Proinflammatory response and mitochondrial dysfunction are related to the pathogenesis of neurodegenerative diseases (NDs). Nuclear factor κB (NFκB) activation has been shown to exaggerate proinflammation and mitochondrial dysfunction, which underlies NDs. CDGSH iron-sulfur domain 2 (CISD2) has been shown to be associated with peroxisome proliferator-activated receptor-β (PPAR-β) to compete for NFκB and antagonize the two aforementioned NFκB-provoked pathogeneses. Therefore, CISD2-based strategies hold promise in the treatment of NDs. CISD2 protein belongs to the human NEET protein family and is encoded by the CISD2 gene (located at 4q24 in humans). In CISD2, the [2Fe-2S] cluster, through coordinates of 3-cysteine-1-histidine on the CDGSH domain, acts as a homeostasis regulator under environmental stress through the transfer of electrons or iron-sulfur clusters. Here, we have summarized the features of CISD2 in genetics and clinics, briefly outlined the role of CISD2 as a key physiological regulator, and presented modalities to increase CISD2 activity, including biomedical engineering or pharmacological management. Strategies to increase CISD2 activity can be beneficial for the prevention of inflammation and mitochondrial dysfunction, and thus, they can be applied in the management of NDs. Full article
(This article belongs to the Special Issue Genetics of Neurodegenerative Diseases 2.0)
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23 pages, 4029 KiB  
Review
WWOX Loss of Function in Neurodevelopmental and Neurodegenerative Disorders
by C. Marcelo Aldaz and Tabish Hussain
Int. J. Mol. Sci. 2020, 21(23), 8922; https://doi.org/10.3390/ijms21238922 - 24 Nov 2020
Cited by 28 | Viewed by 4363
Abstract
The WWOX gene was initially discovered as a putative tumor suppressor. More recently, its association with multiple central nervous system (CNS) pathologies has been recognized. WWOX biallelic germline pathogenic variants have been implicated in spinocerebellar ataxia type 12 (SCAR12; MIM:614322) and in early [...] Read more.
The WWOX gene was initially discovered as a putative tumor suppressor. More recently, its association with multiple central nervous system (CNS) pathologies has been recognized. WWOX biallelic germline pathogenic variants have been implicated in spinocerebellar ataxia type 12 (SCAR12; MIM:614322) and in early infantile epileptic encephalopathy (EIEE28; MIM:616211). WWOX germline copy number variants have also been associated with autism spectrum disorder (ASD). All identified germline genomic variants lead to partial or complete loss of WWOX function. Importantly, large-scale genome-wide association studies have also identified WWOX as a risk gene for common neurodegenerative conditions such as Alzheimer’s disease (AD) and multiple sclerosis (MS). Thus, the spectrum of CNS disorders associated with WWOX is broad and heterogeneous, and there is little understanding of potential mechanisms at play. Exploration of gene expression databases indicates that WWOX expression is comparatively higher in the human cerebellar cortex than in other CNS structures. However, RNA in-situ hybridization data from the Allen Mouse Brain Atlas show that specific regions of the basolateral amygdala (BLA), the medial entorhinal cortex (EC), and deep layers of the isocortex can be singled out as brain regions with specific higher levels of Wwox expression. These observations are in close agreement with single-cell RNA-seq data which indicate that neurons from the medial entorhinal cortex, Layer 5 from the frontal cortex as well as GABAergic basket cells and granule cells from cerebellar cortex are the specific neuronal subtypes that display the highest Wwox expression levels. Importantly, the brain regions and cell types in which WWOX is most abundantly expressed, such as the EC and BLA, are intimately linked to pathologies and syndromic conditions in turn associated with this gene, such as epilepsy, intellectual disability, ASD, and AD. Higher Wwox expression in interneurons and granule cells from cerebellum points to a direct link to the described cerebellar ataxia in cases of WWOX loss of function. We now know that total or partial impairment of WWOX function results in a wide and heterogeneous variety of neurodegenerative conditions for which the specific molecular mechanisms remain to be deciphered. Nevertheless, these observations indicate an important functional role for WWOX in normal development and function of the CNS. Evidence also indicates that disruption of WWOX expression at the gene or protein level in CNS has significant deleterious consequences. Full article
(This article belongs to the Special Issue Genetics of Neurodegenerative Diseases 2.0)
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15 pages, 877 KiB  
Review
Genetic Variants of Lipoprotein Lipase and Regulatory Factors Associated with Alzheimer’s Disease Risk
by Kimberley D. Bruce, Maoping Tang, Philip Reigan and Robert H. Eckel
Int. J. Mol. Sci. 2020, 21(21), 8338; https://doi.org/10.3390/ijms21218338 - 06 Nov 2020
Cited by 18 | Viewed by 3757
Abstract
Lipoprotein lipase (LPL) is a key enzyme in lipid and lipoprotein metabolism. The canonical role of LPL involves the hydrolysis of triglyceride-rich lipoproteins for the provision of FFAs to metabolic tissues. However, LPL may also contribute to lipoprotein uptake by acting as a [...] Read more.
Lipoprotein lipase (LPL) is a key enzyme in lipid and lipoprotein metabolism. The canonical role of LPL involves the hydrolysis of triglyceride-rich lipoproteins for the provision of FFAs to metabolic tissues. However, LPL may also contribute to lipoprotein uptake by acting as a molecular bridge between lipoproteins and cell surface receptors. Recent studies have shown that LPL is abundantly expressed in the brain and predominantly expressed in the macrophages and microglia of the human and murine brain. Moreover, recent findings suggest that LPL plays a direct role in microglial function, metabolism, and phagocytosis of extracellular factors such as amyloid- beta (Aβ). Although the precise function of LPL in the brain remains to be determined, several studies have implicated LPL variants in Alzheimer’s disease (AD) risk. For example, while mutations shown to have a deleterious effect on LPL function and expression (e.g., N291S, HindIII, and PvuII) have been associated with increased AD risk, a mutation associated with increased bridging function (S447X) may be protective against AD. Recent studies have also shown that genetic variants in endogenous LPL activators (ApoC-II) and inhibitors (ApoC-III) can increase and decrease AD risk, respectively, consistent with the notion that LPL may play a protective role in AD pathogenesis. Here, we review recent advances in our understanding of LPL structure and function, which largely point to a protective role of functional LPL in AD neuropathogenesis. Full article
(This article belongs to the Special Issue Genetics of Neurodegenerative Diseases 2.0)
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14 pages, 1092 KiB  
Review
Role of RNA Oxidation in Neurodegenerative Diseases
by Ziqian Liu, Xiatian Chen, Zhe Li, Wei Ye, Hongyan Ding, Peifeng Li and Lynn Htet Htet Aung
Int. J. Mol. Sci. 2020, 21(14), 5022; https://doi.org/10.3390/ijms21145022 - 16 Jul 2020
Cited by 17 | Viewed by 3174
Abstract
In the history of nucleic acid research, DNA has always been the main research focus. After the sketch of the human genome was completed in 2000, RNA has been started to gain more attention due to its abundancies in the cell and its [...] Read more.
In the history of nucleic acid research, DNA has always been the main research focus. After the sketch of the human genome was completed in 2000, RNA has been started to gain more attention due to its abundancies in the cell and its essential role in cellular physiology and pathologies. Recent studies have shown that RNAs are susceptible to oxidative damage and oxidized RNA is able to break the RNA strand, and affect the protein synthesis, which can lead to cell degradation and cell death. Studies have shown that RNA oxidation is one of the early events in the formation and development of neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. However, its molecular mechanism, as well as its impact on these diseases, are still unclear. In this article, we review the different types of RNA oxidative damage and the neurodegenerative diseases that are reported to be associated with RNA oxidative damage. In addition, we discuss recent findings on the association between RNA oxidative damage and the development of neurodegenerative diseases, which will have great significance for the development of novel strategies for the prevention and treatment of these diseases. Full article
(This article belongs to the Special Issue Genetics of Neurodegenerative Diseases 2.0)
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28 pages, 2638 KiB  
Review
Modeling Neurodegenerative Disorders in Drosophila melanogaster
by Harris Bolus, Kassi Crocker, Grace Boekhoff-Falk and Stanislava Chtarbanova
Int. J. Mol. Sci. 2020, 21(9), 3055; https://doi.org/10.3390/ijms21093055 - 26 Apr 2020
Cited by 59 | Viewed by 11990
Abstract
Drosophila melanogaster provides a powerful genetic model system in which to investigate the molecular mechanisms underlying neurodegenerative diseases. In this review, we discuss recent progress in Drosophila modeling Alzheimer’s Disease, Parkinson’s Disease, Amyotrophic Lateral Sclerosis (ALS), Huntington’s Disease, Ataxia Telangiectasia, and neurodegeneration related [...] Read more.
Drosophila melanogaster provides a powerful genetic model system in which to investigate the molecular mechanisms underlying neurodegenerative diseases. In this review, we discuss recent progress in Drosophila modeling Alzheimer’s Disease, Parkinson’s Disease, Amyotrophic Lateral Sclerosis (ALS), Huntington’s Disease, Ataxia Telangiectasia, and neurodegeneration related to mitochondrial dysfunction or traumatic brain injury. We close by discussing recent progress using Drosophila models of neural regeneration and how these are likely to provide critical insights into future treatments for neurodegenerative disorders. Full article
(This article belongs to the Special Issue Genetics of Neurodegenerative Diseases 2.0)
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8 pages, 1061 KiB  
Case Report
PSEN1 Compound Heterozygous Mutations Associated with Cerebral Amyloid Angiopathy and Cognitive Decline Phenotype
by Ilaria Palmieri, Marialuisa Valente, Lisa Maria Farina, Simone Gana, Brigida Minafra, Roberta Zangaglia, Orietta Pansarasa, Daisy Sproviero, Alfredo Costa, Claudio Pacchetti, Anna Pichiecchio, Stella Gagliardi and Cristina Cereda
Int. J. Mol. Sci. 2021, 22(8), 3870; https://doi.org/10.3390/ijms22083870 - 08 Apr 2021
Cited by 5 | Viewed by 2064
Abstract
Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder caused by the deposition of amyloid beta-peptide (Aβ) aggregates. Aβ aggregates lead to vessel rupture and intracerebral hemorrhages, detected by magnetic resonance imaging (MRI). Presenile CAA is usually genetically determined by mutations in the amyloid [...] Read more.
Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder caused by the deposition of amyloid beta-peptide (Aβ) aggregates. Aβ aggregates lead to vessel rupture and intracerebral hemorrhages, detected by magnetic resonance imaging (MRI). Presenile CAA is usually genetically determined by mutations in the amyloid precursor protein (APP) gene. However, mutations after codon 200 in the presenilin 1 (PSEN1) gene have been reported to facilitate CAA onset. Here, we analyzed the genetic bases in a patient of 55 years old affected by CAA and cognitive decline. DNA was isolated and genetic analysis was performed by Next-Generation Sequencing (NGS). RNA was extracted and retro-transcribed to perform segregation analysis by TOPO-TA cloning. WB analysis was carried out to check the impact of the mutations on protein. Two compound heterozygous mutations in PSEN1 exon 10, such as a novel stop-gain mutation (c.1070C > G) and a pathogenic splice variant (c.1129A > T), were found by NGS. Both mutations altered the presenilin 1 protein, truncating its C-terminal portion. This is the first case of CAA and cognitive decline caused by two compound mutations in PSEN1. With this report, we suggest extending the genetic analysis to PSEN1 when cerebral microbleeds are observed by MRI investigation in a patient affected by presenile cognitive decline. Full article
(This article belongs to the Special Issue Genetics of Neurodegenerative Diseases 2.0)
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