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Genetics of Neurodegenerative Diseases: Focus on Progression and Response to Treatment

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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 June 2019) | Viewed by 55369

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Dr. Alessio Di Fonzo

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Guest Editor

Neurology Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, 20122 Milan, Italy
Interests: Parkinson’s Disease; Neurogenetics; Genetic Dystonia; Genetic Ataxia

Dr. Cristoforo Comi

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Guest Editor

Department of Translational Medicine, Section of Neurology, University of Piemonte Orientale, 28100 Novara, Italy
Interests: neurodegenerative diseases including Parkinson’s disease; Huntington’s disease; other movement disorders; Alzheimer’s disease; neuroimmune diseases including: multiple sclerosis, inflammatory neuropathies, myasthenia gravis
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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

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Published Papers (9 papers)

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Research

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15 pages, 1657 KiB

Open AccessArticle

Analysis of 50 Neurodegenerative Genes in Clinically Diagnosed Early-Onset Alzheimer’s Disease

by Vo Van Giau, Vorapun Senanarong, Eva Bagyinszky, Seong Soo A. An and SangYun Kim

Int. J. Mol. Sci. 2019, 20(6), 1514; https://doi.org/10.3390/ijms20061514 - 26 Mar 2019

Cited by 52 | Viewed by 6668

Abstract

Alzheimer’s disease (AD), Parkinson’s disease (PD), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), and prion diseases have a certain degree of clinical, pathological, and molecular overlapping. Previous studies revealed that many causative mutations in AD, PD, and FTD/ALS genes could be found in clinical familial and sporadic AD. To further elucidate the missing heritability in early-onset Alzheimer’s disease (EOAD), we genetically characterized a Thai EOAD cohort by Next-Generation Sequencing (NGS) with a high depth of coverage, capturing variants in 50 previously recognized AD and other related disorders’ genes. A novel mutation, APP p.V604M, and the known causative variant, PSEN1 p.E184G, were found in two of the familiar cases. Remarkably, among 61 missense variants were additionally discovered from 21 genes out of 50 genes, six potential mutations including MAPT P513A, LRRK2 p.R1628P, TREM2 p.L211P, and CSF1R (p.P54Q and pL536V) may be considered to be probably/possibly pathogenic and risk factors for other dementia leading to neuronal degeneration. All allele frequencies of the identified missense mutations were compared to 622 control individuals. Our study provides initial evidence that AD and other neurodegenerative diseases may represent shades of the same disease spectrum, and consideration should be given to offer exactly embracing genetic testing to patients diagnosed with EOAD. Our results need to be further confirmed with a larger cohort from this area. Full article

(This article belongs to the Special Issue Genetics of Neurodegenerative Diseases: Focus on Progression and Response to Treatment)

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11 pages, 1853 KiB

Open AccessArticle

The First Report of Polymorphisms and Genetic Features of the prion-like Protein Gene (PRND) in a Prion Disease-Resistant Animal, Dog

by Sae-Young Won, Yong-Chan Kim, Kiwon Kim, An-Dang Kim and Byung-Hoon Jeong

Int. J. Mol. Sci. 2019, 20(6), 1404; https://doi.org/10.3390/ijms20061404 - 20 Mar 2019

Cited by 24 | Viewed by 5709

Abstract

Prion disease has displayed large infection host ranges among several species; however, dogs have not been reported to be infected and are considered prion disease-resistant animals. Case-controlled studies in several species, including humans and cattle, indicated a potent association of prion protein gene (PRNP) polymorphisms in the progression of prion disease. Thus, because of the proximal location and similar structure of the PRNP gene among the prion gene family, the prion-like protein gene (PRND) was noted as a novel candidate gene that contributes to prion disease susceptibility. Several case-controlled studies have confirmed the relationship of the PRND gene with prion disease vulnerability, and strong genetic linkage disequilibrium blocks were identified in prion-susceptible species between the PRNP and PRND genes. However, to date, polymorphisms of the dog PRND gene have not been reported, and the genetic linkage between the PRNP and PRND genes has not been examined thus far. Here, we first investigated dog PRND polymorphisms in 207 dog DNA samples using direct DNA sequencing. A total of four novel single nucleotide polymorphisms (SNPs), including one nonsynonymous SNP (c.149G>A, R50H), were identified in this study. We also found two major haplotypes among the four novel SNPs. In addition, we compared the genotype and allele frequencies of the c.149G>A (R50H) SNP and found significantly different distributions among eight dog breeds. Furthermore, we annotated the c.149G>A (R50H) SNP of the dog PRND gene using in silico tools, PolyPhen-2, PROVEAN, and PANTHER. Finally, we examined linkage disequilibrium between the PRNP and PRND genes in dogs. Interestingly, we did not find a strong genetic linkage between these two genes. To the best of our knowledge, this was the first genetic study of the PRND gene in a prion disease-resistant animal, a dog. Full article

(This article belongs to the Special Issue Genetics of Neurodegenerative Diseases: Focus on Progression and Response to Treatment)

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Review

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16 pages, 919 KiB

Open AccessReview

Microbiome Influence in the Pathogenesis of Prion and Alzheimer’s Diseases

by Valeria D’Argenio and Daniela Sarnataro

Int. J. Mol. Sci. 2019, 20(19), 4704; https://doi.org/10.3390/ijms20194704 - 23 Sep 2019

Cited by 53 | Viewed by 7573

Abstract

Misfolded and abnormal β-sheets forms of wild-type proteins, such as cellular prion protein (PrP^C) and amyloid beta (Aβ), are believed to be the vectors of neurodegenerative diseases, prion and Alzheimer’s disease (AD), respectively. Increasing evidence highlights the “prion-like” seeding of protein aggregates as a mechanism for pathological spread in AD, tauopathy, as well as in other neurodegenerative diseases, such as Parkinson’s. Mutations in both PrP^C and Aβ precursor protein (APP), have been associated with the pathogenesis of these fatal disorders with clear evidence for their pathogenic significance. In addition, a critical role for the gut microbiota is emerging; indeed, as a consequence of gut–brain axis alterations, the gut microbiota has been involved in the regulation of Aβ production in AD and, through the microglial inflammation, in the amyloid fibril formation, in prion diseases. Here, we aim to review the role of microbiome (“the other human genome”) alterations in AD and prion disease pathogenesis. Full article

(This article belongs to the Special Issue Genetics of Neurodegenerative Diseases: Focus on Progression and Response to Treatment)

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27 pages, 1792 KiB

Open AccessReview

Genetic Factors of Cerebral Small Vessel Disease and Their Potential Clinical Outcome

by Vo Van Giau, Eva Bagyinszky, Young Chul Youn, Seong Soo A. An and Sang Yun Kim

Int. J. Mol. Sci. 2019, 20(17), 4298; https://doi.org/10.3390/ijms20174298 - 3 Sep 2019

Cited by 25 | Viewed by 7188

Abstract

Cerebral small vessel diseases (SVD) have been causally correlated with ischemic strokes, leading to cognitive decline and vascular dementia. Neuroimaging and molecular genetic tests could improve diagnostic accuracy in patients with potential SVD. Several types of monogenic, hereditary cerebral SVD have been identified: cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cathepsin A-related arteriopathy with strokes and leukoencephalopathy (CARASAL), hereditary diffuse leukoencephalopathy with spheroids (HDLS), COL4A1/2-related disorders, and Fabry disease. These disorders can be distinguished based on their genetics, pathological and imaging findings, clinical manifestation, and diagnosis. Genetic studies of sporadic cerebral SVD have demonstrated a high degree of heritability, particularly among patients with young-onset stroke. Common genetic variants in monogenic disease may contribute to pathological progress in several cerebral SVD subtypes, revealing distinct genetic mechanisms in different subtype of SVD. Hence, genetic molecular analysis should be used as the final gold standard of diagnosis. The purpose of this review was to summarize the recent discoveries made surrounding the genetics of cerebral SVD and their clinical significance, to provide new insights into the pathogenesis of cerebral SVD, and to highlight the possible convergence of disease mechanisms in monogenic and sporadic cerebral SVD. Full article

(This article belongs to the Special Issue Genetics of Neurodegenerative Diseases: Focus on Progression and Response to Treatment)

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20 pages, 1185 KiB

Open AccessReview

Emerging Role of Genetic Alterations Affecting Exosome Biology in Neurodegenerative Diseases

by Paola Riva, Cristina Battaglia and Marco Venturin

Int. J. Mol. Sci. 2019, 20(17), 4113; https://doi.org/10.3390/ijms20174113 - 23 Aug 2019

Cited by 26 | Viewed by 6088

Abstract

The abnormal deposition of proteins in brain tissue is a common feature of neurodegenerative diseases (NDs) often accompanied by the spread of mutated proteins, causing neuronal toxicity. Exosomes play a fundamental role on their releasing in extracellular space after endosomal pathway activation, allowing to remove protein aggregates by lysosomal degradation or their inclusion into multivesicular bodies (MVBs), besides promoting cellular cross-talk. The emerging evidence of pathogenic mutations associated to ND susceptibility, leading to impairment of exosome production and secretion, opens a new perspective on the mechanisms involved in neurodegeneration. Recent findings suggest to investigate the genetic mechanisms regulating the different exosome functions in central nervous system (CNS), to understand their role in the pathogenesis of NDs, addressing the identification of diagnostic and pharmacological targets. This review aims to summarize the mechanisms underlying exosome biogenesis, their molecular composition and functions in CNS, with a specific focus on the recent findings invoking a defective exosome biogenesis as a common biological feature of the major NDs, caused by genetic alterations. Further definition of the consequences of specific genetic mutations on exosome biogenesis and release will improve diagnostic and pharmacological studies in NDs. Full article

(This article belongs to the Special Issue Genetics of Neurodegenerative Diseases: Focus on Progression and Response to Treatment)

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17 pages, 1192 KiB

Open AccessReview

Expression of HERV Genes as Possible Biomarker and Target in Neurodegenerative Diseases

by Antonina Dolei, Gabriele Ibba, Claudia Piu and Caterina Serra

Int. J. Mol. Sci. 2019, 20(15), 3706; https://doi.org/10.3390/ijms20153706 - 29 Jul 2019

Cited by 25 | Viewed by 6135

Abstract

Human endogenous retroviruses (HERVs) are genetic parasites, in-between genetics and environment. Few HERVs retain some coding capability. Sometimes, the host has the advantage of some HERV genes; conversely, HERVs may contribute to pathogenesis. The expression of HERVs depends on several factors, and is regulated epigenetically by stimuli such as inflammation, viral and microbial infections, etc. Increased expression of HERVs occurs in physiological and pathological conditions, in one or more body sites. Several diseases have been attributed to one or more HERVs, particularly neurological diseases. The key problem is to differentiate the expression of a HERV as cause or effect of a disease. To be used as a biomarker, a correlation between the expression of a certain HERV and the disease onset and/or behavior must be found. The greater challenge is to establish a pathogenic role. The criteria defining causal connections between HERVs and diseases include the development of animal models, and disease modulation in humans, by anti-HERV therapeutic antibody. So far, statistically significant correlations between HERVs and diseases have been achieved for HERV-W and multiple sclerosis; disease reproduction in transgenic animals was achieved for HERV-W and multiple sclerosis, and for HERV-K and amyotrophic lateral sclerosis. Clinical trials for both diseases are in progress. Full article

(This article belongs to the Special Issue Genetics of Neurodegenerative Diseases: Focus on Progression and Response to Treatment)

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14 pages, 1904 KiB

Open AccessReview

Lessons on Differential Neuronal-Death-Vulnerability from Familial Cases of Parkinson’s and Alzheimer’s Diseases

by Rafael Franco, Gemma Navarro and Eva Martínez-Pinilla

Int. J. Mol. Sci. 2019, 20(13), 3297; https://doi.org/10.3390/ijms20133297 - 4 Jul 2019

Cited by 8 | Viewed by 4326

Abstract

The main risk of Alzheimer’s disease (AD) and Parkinson’s disease (PD), the two most common neurodegenerative pathologies, is aging. In contrast to sporadic cases, whose symptoms appear at >60 years of age, familial PD or familial AD affects younger individuals. Finding early biological markers of these diseases as well as efficacious treatments for both symptom relief and delaying disease progression are of paramount relevance. Familial early-onset PD/AD are due to genetic factors, sometimes a single mutation in a given gene. Both diseases have neuronal loss and abnormal accumulations of specific proteins in common, but in different brain regions. Despite shared features, the mechanisms underlying the pathophysiological processes are not known. This review aims at finding, among the genetic-associated cases of PD and AD, common trends that could be of interest to discover reliable biomarkers and efficacious therapies, especially those aimed at affording neuroprotection, i.e., the prevention of neuronal death. Full article

(This article belongs to the Special Issue Genetics of Neurodegenerative Diseases: Focus on Progression and Response to Treatment)

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24 pages, 727 KiB

Open AccessReview

Fishing in the Cell Powerhouse: Zebrafish as A Tool for Exploration of Mitochondrial Defects Affecting the Nervous System

by Gianluca Fichi, Valentina Naef, Amilcare Barca, Giovanna Longo, Baldassare Fronte, Tiziano Verri, Filippo M. Santorelli, Maria Marchese and Vittoria Petruzzella

Int. J. Mol. Sci. 2019, 20(10), 2409; https://doi.org/10.3390/ijms20102409 - 15 May 2019

Cited by 16 | Viewed by 6543

Abstract

The zebrafish (Danio rerio) is a small vertebrate ideally suited to the modeling of human diseases. Large numbers of genetic alterations have now been modeled and could be used to study organ development by means of a genetic approach. To date, limited attention has been paid to the possible use of the zebrafish toolbox in studying human mitochondrial disorders affecting the nervous system. Here, we review the pertinent scientific literature discussing the use of zebrafish in modeling gene mutations involved in mitochondria-related neurological human diseases. A critical analysis of the literature suggests that the zebrafish not only lends itself to exploration of the pathological consequences of mitochondrial energy output on the nervous system but could also serve as an attractive platform for future drugs in an as yet untreatable category of human disorders. Full article

(This article belongs to the Special Issue Genetics of Neurodegenerative Diseases: Focus on Progression and Response to Treatment)

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Other

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6 pages, 761 KiB

Open AccessCase Report

MCEE Mutations in an Adult Patient with Parkinson’s Disease, Dementia, Stroke and Elevated Levels of Methylmalonic Acid

by Mattias Andréasson, Rolf H. Zetterström, Ulrika von Döbeln, Anna Wedell and Per Svenningsson

Int. J. Mol. Sci. 2019, 20(11), 2631; https://doi.org/10.3390/ijms20112631 - 29 May 2019

Cited by 6 | Viewed by 3935

Abstract

Methylmalonic aciduria (MMA-uria) is seen in several inborn errors of metabolism (IEM) affecting intracellular cobalamin pathways. Methylmalonyl-CoA epimerase (MCE) is an enzyme involved in the mitochondrial cobalamin-dependent pathway generating succinyl-CoA. Homozygous mutations in the corresponding MCEE gene have been shown in children to cause MCE deficiency with isolated MMA-uria and a variable clinical phenotype. We describe a 78-year-old man with Parkinson’s disease, dementia and stroke in whom elevated serum levels of methylmalonic acid had been evident for many years. Metabolic work-up revealed intermittent MMA-uria and increased plasma levels of propionyl-carnitine not responsive to treatment with high-dose hydroxycobalamin. Whole genome sequencing was performed, with data analysis targeted towards genes known to cause IEM. Compound heterozygous mutations were identified in the MCEE gene, c.139C>T (p.Arg47X) and c.419delA (p.Lys140fs), of which the latter is novel. To our knowledge, this is the first report of an adult patient with MCEE mutations and MMA-uria, thus adding novel data to the possible phenotypical spectrum of MCE deficiency. Although clinical implications are uncertain, it can be speculated whether intermittent hyperammonemia during episodes of metabolic stress could have precipitated the patient’s ongoing neurodegeneration attributed to Parkinson’s disease. Full article

(This article belongs to the Special Issue Genetics of Neurodegenerative Diseases: Focus on Progression and Response to Treatment)

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