Perspectives and Opportunities for ALS in the “Omics” Era

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 (28 February 2020) | Viewed by 22128

Special Issue Editors

Unit of Medical Genetics, Section of Genomic Medicine, Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
Interests: medical genomics; clinical genetics; bioinformatics; amyotrophic lateral sclerosis; developmental disorders
Special Issues, Collections and Topics in MDPI journals
Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy
Interests: neurodegeneration; amyotrophic lateral sclerosis; human genetics; animal models of genetic diseases; zebrafish
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Amyotrophic lateral sclerosis (ALS) is an invariably lethal neurodegenerative disorder characterized by the progressive loss of motor neurons. Despite considerable scientific efforts and significant progress over the last decades, many aspects of the underlying pathogenic mechanisms remain unresolved, and no effective therapy is available yet.

Genetic factors are recognized to play a relevant role in ALS, and the recent outbreak of high-throughput genetic analysis techniques has led to the identification of a new series of genes claiming some association with ALS. Nonetheless, the genetic architecture of ALS appears to be complex, and variants of currently known genes account for only a fraction of the estimated heritability of ALS, explaining 40%–80% of familial ALS, but only 5%–15% of sporadic ALS.

The whole scenario is further complicated by the fact that several genes involved in ALS may also be primarily responsible for other neurological and non-neurological conditions. ALS itself has heterogeneous clinical presentation, with varying involvement of the central nervous system and multiple pathophysiological mechanisms that must be taken into account.

In this Special Issue, we aim to gather together both the extensive reviews and innovative research that explore the changing landscape of ALS diagnosis and therapy in the current era of fast-growing molecular investigation methods. Proposed topics include, but are not limited to, the following aspects:

  • ALS-related genes and their possibly diverse roles in determining or modifying different ALS clinical presentations and other associated diseases;
  • New strategies for the identification and pathogenic assessment of genetic factors underlying ALS, specifically considering the contribution from high-throughput sequencing methods;
  • Interactions between genetic and environmental factors in the etiopathogenesis of ALS. Scientific approaches for the identification and validation of such risk factors based on the availability of large datasets from high-throughput genotyping studies (e.g., Mendelian randomization);
  • The role of “omics” technologies (from transcriptomics to proteomics, from microbiomics to pharmacogenomics, etc.) in untangling the genetic architecture of ALS, the underlying pathophysiological processes, the nosology, and the relationship between ALS and other neurological conditions with a partially shared basis (including, for instance, frontotemporal dementia);
  • The definition of reliable biomarkers to detect ALS at the early disease stage, to help with differential diagnosis and, moreover, to provide a useful tool for stratifying and monitoring patients with ALS in clinical trials;
  • The development of innovative therapeutic strategies tailored to ALS patients’ individual genetic makeup in view of the rapidly developing field of personalized medicine;
  • Future perspectives and opportunities in ALS research as a consequence of the implementation of new approaches based on the various “omics” technologies.

Dr. Giuseppe Marangi
Dr. Serena Lattante
Guest Editors

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Keywords

  • Amyotrophic lateral sclerosis
  • ALS pathophysiology
  • Biomarker
  • Genomics
  • High-throughput genetic analysis
  • Missing heritability
  • Oligogenic inheritance
  • Environmental risk factors
  • Polygenic risk
  • Personalized medicine

Published Papers (5 papers)

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Research

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31 pages, 2074 KiB  
Article
High-Throughput Genetic Testing in ALS: The Challenging Path of Variant Classification Considering the ACMG Guidelines
by Serena Lattante, Giuseppe Marangi, Paolo Niccolò Doronzio, Amelia Conte, Giulia Bisogni, Marcella Zollino and Mario Sabatelli
Genes 2020, 11(10), 1123; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11101123 - 24 Sep 2020
Cited by 14 | Viewed by 4404
Abstract
The development of high-throughput sequencing technologies and screening of big patient cohorts with familial and sporadic amyotrophic lateral sclerosis (ALS) led to the identification of a significant number of genetic variants, which are sometimes difficult to interpret. The American College of Medical Genetics [...] Read more.
The development of high-throughput sequencing technologies and screening of big patient cohorts with familial and sporadic amyotrophic lateral sclerosis (ALS) led to the identification of a significant number of genetic variants, which are sometimes difficult to interpret. The American College of Medical Genetics and Genomics (ACMG) provided guidelines to help molecular geneticists and pathologists to interpret variants found in laboratory testing. We assessed the application of the ACMG criteria to ALS-related variants, combining data from literature with our experience. We analyzed a cohort of 498 ALS patients using massive parallel sequencing of ALS-associated genes and identified 280 variants with a minor allele frequency < 1%. Examining all variants using the ACMG criteria, thus considering the type of variant, inheritance, familial segregation, and possible functional studies, we classified 20 variants as “pathogenic”. In conclusion, ALS’s genetic complexity, such as oligogenic inheritance, presence of genes acting as risk factors, and reduced penetrance, needs to be considered when interpreting variants. The goal of this work is to provide helpful suggestions to geneticists and clinicians dealing with ALS. Full article
(This article belongs to the Special Issue Perspectives and Opportunities for ALS in the “Omics” Era)
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17 pages, 1206 KiB  
Article
A Knowledge-Based Machine Learning Approach to Gene Prioritisation in Amyotrophic Lateral Sclerosis
by Daniel M. Bean, Ammar Al-Chalabi, Richard J. B. Dobson and Alfredo Iacoangeli
Genes 2020, 11(6), 668; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11060668 - 19 Jun 2020
Cited by 16 | Viewed by 4514
Abstract
Amyotrophic lateral sclerosis is a neurodegenerative disease of the upper and lower motor neurons resulting in death from neuromuscular respiratory failure, typically within two to five years of first symptoms. Several rare disruptive gene variants have been associated with ALS and are responsible [...] Read more.
Amyotrophic lateral sclerosis is a neurodegenerative disease of the upper and lower motor neurons resulting in death from neuromuscular respiratory failure, typically within two to five years of first symptoms. Several rare disruptive gene variants have been associated with ALS and are responsible for about 15% of all cases. Although our knowledge of the genetic landscape of this disease is improving, it remains limited. Machine learning models trained on the available protein–protein interaction and phenotype-genotype association data can use our current knowledge of the disease genetics for the prediction of novel candidate genes. Here, we describe a knowledge-based machine learning method for this purpose. We trained our model on protein–protein interaction data from IntAct, gene function annotation from Gene Ontology, and known disease-gene associations from DisGeNet. Using several sets of known ALS genes from public databases and a manual review as input, we generated a list of new candidate genes for each input set. We investigated the relevance of the predicted genes in ALS by using the available summary statistics from the largest ALS genome-wide association study and by performing functional and phenotype enrichment analysis. The predicted sets were enriched for genes associated with other neurodegenerative diseases known to overlap with ALS genetically and phenotypically, as well as for biological processes associated with the disease. Moreover, using ALS genes from ClinVar and our manual review as input, the predicted sets were enriched for ALS-associated genes (ClinVar p = 0.038 and manual review p = 0.060) when used for gene prioritisation in a genome-wide association study. Full article
(This article belongs to the Special Issue Perspectives and Opportunities for ALS in the “Omics” Era)
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10 pages, 986 KiB  
Article
A Study of Gene Expression Changes in Human Spinal and Oculomotor Neurons; Identifying Potential Links to Sporadic ALS
by Aayan N. Patel and Dennis Mathew
Genes 2020, 11(4), 448; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11040448 - 20 Apr 2020
Cited by 2 | Viewed by 5946
Abstract
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that causes compromised function of motor neurons and neuronal death. However, oculomotor neurons are largely spared from disease symptoms. The underlying causes for sporadic ALS as well as for the resistance of oculomotor neurons to [...] Read more.
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that causes compromised function of motor neurons and neuronal death. However, oculomotor neurons are largely spared from disease symptoms. The underlying causes for sporadic ALS as well as for the resistance of oculomotor neurons to disease symptoms remain poorly understood. In this bioinformatic-analysis, we compared the gene expression profiles of spinal and oculomotor tissue samples from control individuals and sporadic ALS patients. We show that the genes GAD2 and GABRE (involved in GABA signaling), and CALB1 (involved in intracellular Ca2+ ion buffering) are downregulated in the spinal tissues of ALS patients, but their endogenous levels are higher in oculomotor tissues relative to the spinal tissues. Our results suggest that the downregulation of these genes and processes in spinal tissues are related to sporadic ALS disease progression and their upregulation in oculomotor neurons confer upon them resistance to ALS symptoms. These results build upon prevailing models of excitotoxicity that are relevant to sporadic ALS disease progression and point out unique opportunities for better understanding the progression of neurodegenerative properties associated with sporadic ALS. Full article
(This article belongs to the Special Issue Perspectives and Opportunities for ALS in the “Omics” Era)
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Review

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15 pages, 664 KiB  
Review
Metabolomics: A Tool to Understand the Impact of Genetic Mutations in Amyotrophic Lateral Sclerosis
by Débora Lanznaster, Charlotte Veyrat-Durebex, Patrick Vourc’h, Christian R. Andres, Hélène Blasco and Philippe Corcia
Genes 2020, 11(5), 537; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11050537 - 11 May 2020
Cited by 11 | Viewed by 3300
Abstract
Metabolomics studies performed in patients with amyotrophic lateral sclerosis (ALS) reveal a set of distinct metabolites that can shed light on the pathological alterations taking place in each individual. Metabolites levels are influenced by disease status, and genetics play an important role both [...] Read more.
Metabolomics studies performed in patients with amyotrophic lateral sclerosis (ALS) reveal a set of distinct metabolites that can shed light on the pathological alterations taking place in each individual. Metabolites levels are influenced by disease status, and genetics play an important role both in familial and sporadic ALS cases. Metabolomics analysis helps to unravel the differential impact of the most common ALS-linked genetic mutations (as C9ORF72, SOD1, TARDBP, and FUS) in specific signaling pathways. Further, studies performed in genetic models of ALS reinforce the role of TDP-43 pathology in the vast majority of ALS cases. Studies performed in differentiated cells from ALS-iPSC (induced Pluripotent Stem Cells) reveal alterations in the cell metabolism that are also found in ALS models and ultimately in ALS patients. The development of metabolomics approaches in iPSC derived from ALS patients allow addressing and ultimately understanding the pathological mechanisms taking place in any patient. Lately, the creation of a “patient in a dish” will help to identify patients that may benefit from specific treatments and allow the implementation of personalized medicine. Full article
(This article belongs to the Special Issue Perspectives and Opportunities for ALS in the “Omics” Era)
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22 pages, 313 KiB  
Review
Existing and Emerging Metabolomic Tools for ALS Research
by Christine Germeys, Tijs Vandoorne, Valérie Bercier and Ludo Van Den Bosch
Genes 2019, 10(12), 1011; https://0-doi-org.brum.beds.ac.uk/10.3390/genes10121011 - 05 Dec 2019
Cited by 9 | Viewed by 3410
Abstract
Growing evidence suggests that aberrant energy metabolism could play an important role in the pathogenesis of amyotrophic lateral sclerosis (ALS). Despite this, studies applying advanced technologies to investigate energy metabolism in ALS remain scarce. The rapidly growing field of metabolomics offers exciting new [...] Read more.
Growing evidence suggests that aberrant energy metabolism could play an important role in the pathogenesis of amyotrophic lateral sclerosis (ALS). Despite this, studies applying advanced technologies to investigate energy metabolism in ALS remain scarce. The rapidly growing field of metabolomics offers exciting new possibilities for ALS research. Here, we review existing and emerging metabolomic tools that could be used to further investigate the role of metabolism in ALS. A better understanding of the metabolic state of motor neurons and their surrounding cells could hopefully result in novel therapeutic strategies. Full article
(This article belongs to the Special Issue Perspectives and Opportunities for ALS in the “Omics” Era)
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