Conforti, FL

Houlden, H

Renton, AE

English

UCL Discovery

EDITORIALpublished: 23 April 2021doi: 10.3389/fnins.2021.680185Frontiers in Neuroscience | www.frontiersin.org 1 April 2021 | Volume 15 | Article 680185Edited and reviewed by:Ka Wan Li,Vrije UniversiteitAmsterdam, Netherlands*Correspondence:Francesca Luisa Confortifrancescaluisa.conforti@cnr.it;francescaluisa.conforti@unical.itSpecialty section:This article was submitted toNeurogenomics,a section of the journalFrontiers in NeuroscienceReceived: 13 March 2021Accepted: 29 March 2021Published: 23 April 2021Citation:Conforti FL, Renton AE and Houlden H(2021) Editorial: Multifaceted Genes inAmyotrophic LateralSclerosis-Frontotemporal Dementia.Front. Neurosci. 15:680185.doi: 10.3389/fnins.2021.680185Editorial: Multifaceted Genes inAmyotrophic LateralSclerosis-Frontotemporal DementiaFrancesca Luisa Conforti 1*, Alan Edward Renton 2 and Henry Houlden 31Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy, 2 Ronald M. Loeb Center forAlzheimer L Disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States, 3Department of NeuromuscularDisorders, Institute of Neurology, University College London, London, United KingdomKeywords: amyotrophic lateral sclerosis, ALS-FTD spectrum, genetics, genomics, omicsEditorial on the Research TopicMultifaceted Genes in Amyotrophic Lateral Sclerosis-Frontotemporal DementiaAmyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) is a heterogeneous,multi-factorial, and multi-system disease spectrum currently lacking effective drug treatments.The fields of ALS-FTD genetics and genomics have greatly expanded since the first disease geneSOD1 was identified in 1993 (Rosen et al., 1993). The advent of high-throughput next generationsequencing technologies has enabled systematic genome-wide interrogation of genetic variation,implicating disease-causing and disease-modifying genetic loci and improving our understandingof the diverse pathogenic basis of ALS-FTD. Over 30 genetic loci have been reproducibly linkedor associated with ALS-FTD and novel loci continue to be identified (Chia et al., 2018; Guerreiroet al., 2020). It is now recognized that ALS and FTD constitute a disease spectrum or syndromerather than distinct disorders. This scenario exemplifies the emerging observation of phenotypicpleiotropy, where mutations in the same gene give rise to diverse phenotypes, further increasingthe complexity of genotype-phenotype correlation.In 2011, the discovery that theC9orf72GGGGCC repeat expansion (C9-RE) is themost frequentgenetic cause of ALS and FTD definitively consolidated the hypothesis that the two diseasesbelong to the same clinicopathological spectrum (DeJesus-Hernandez et al., 2011; Renton et al.,2011). Repeat expansions have emerged in recent years as major contributors to motor neurondegeneration and with the advent of long-read sequencing, further expansions are likely to bediscovered. Intermediate-length CAG repeat expansions in both ATXN1 (Conforti et al., 2012;Tazelaar et al., 2020) and ATXN2 (Elden et al., 2010) have also been associated with an increasedrisk of developing ALS. Mutations in OPTN, VCP, SQTM1, MATR3, and NEK1 have offeredinsight into the connections between ALS-FTD and seemingly unrelated clinical disorders suchas Paget’s disease and myopathy (Chia et al., 2018). Recently, KIF5A, a gene previously linked totwo rare neurodegenerative disorders, hereditary spastic paraplegia type 10 and Charcot-Marie-Tooth type 2, has been definitively linked to ALS (Brenner et al., 2018; Nicolas et al., 2018). Takentogether, these and other genes have highlighted the complex genetic architecture of ALS-FTD,with many genes in seemingly unrelated or distantly related physiological pathways producing asimilar phenotype.This Research Topic includes significant focus on the C9-RE in ALS and FTD patients. Trojsiet al. studied the C9-RE in a large Italian ALS cohort. They reported C9-RE carriers exhibit ALSsymptoms clinically distinct from sporadic ALS (sALS) patients and, found male but not femaleexpansion carriers have decreased survival, suggesting a potential link between sex and diseaseprogression. Esselin et al. described a large French ALS-FTD cohort with C9-RE. They observedConforti et al. Editorial: Multifaceted Genes in ALS-FTDC9 patients have an earlier age of onset compared to sALSpatients, familial index cases and their siblings have an earlierage of onset compared to their parental generation suggestinganticipation, a predominant female transmission, and a highfrequency of suicides in relatives. Trageser et al. reviewed the roleof immune cell activation in ALS-FTD in the context of the C9-RE, providing an overview of C9-linked ALS-FTD pathogenesisand the interplay of these cellular events with the immune system.The authors suggested the C9-RE mediates neuroinflammatorymechanisms that significantly contribute to pathogenesis andrepresent promising new therapeutic approaches.This Topic also concentrates on overlapping and discordantgenetics across ALS, FTD and other disorders. Tripolszki et al.contributed with their first comprehensive genetic analysis ofthe Hungarian ALS population, highlighting the necessity forlarge-scale studies to distinguish true causative genetic variantsfrom irrelevant ones and accurately uncover the genetic patternof ALS. Abramzon et al. described genes involved both in ALSand FTD as key players in dysfunctional pathways such asRNA processing, autophagy, vesicle trafficking, mitochondria,and protein homeostasis. Due to such significant genetic overlapbetween ALS and FTD, the authors recommended looking inFTD cases for mutations in ALS genes and vice-versa. On theother hand, Ranganathan et al. highlighted that some genesare linked with only ALS or FTD, such as SOD1 and MAPT.This distinction is reflected in the neuropathology, becausemost types of monogenic ALS, C9-FTD, and GRN-FTD arecharacterized by TDP-43-positive inclusions but SOD1-ALS andMAPT-FTD are not, underscoring the need to consider diseasesubtypes when conducting biomarker and therapeutic research.The authors discussed using next generation sequencing toidentify multiple variants in disease-associated genes within anindividual, emphasizing the importance of genomic data tofacilitate a precision medicine approach for treating ALS-FTD.Furthermore, Broce et al. discussed how shifting our focus fromstudying ALS and FTD in isolation to identifying the commonand distinct biological mechanisms that drive these diseaseswill improve treatment discovery and therapeutic development.Hence whole genome sequencing of large international ALS-FTDcohorts will begin to fully understand the genetic contributionto disease, particularly when large collaborative cohorts aresequenced such as in project MinE. Rich et al. suggestedgenome-wide association studies and rare variant associationstudies represent an attractive option for novel gene discoverybecause they do not require prior knowledge or hypotheses.Lower-penetrance alleles identified via association studies mayinform important components of future combinatorial gene-targeted therapies.Additionally, the field shows increasing interest in omicsbioinformatic analysis to elucidate ALS complex moleculararchitecture and its role in clinical heterogeneity. Lin et al.compared gene expression profiles of sALS and controlmotor neurons to discover differentially expressed genes thenidentified pathways and regulators underlying sALS. They founddifferentially expressed genes are enriched for the extracellularmatrix and implicated the NF-κB regulatory pathway insALS pathogenesis. Finally, Morello et al. discussed themost significant contributions of omics approaches (genomics,transcriptomics, proteomics, and metabolomics) in unravelingthe biological complexity of ALS, highlighting how holisticsystems biology approaches and multi-omics data integrationare ideal to provide comprehensive characterization of patient-specific molecular signatures that could potentially guidetherapeutic decisions.The 10 articles in this Research Topic provide an overview ofthe current state of the art in ALS-FTD genetics and genomics,aiming to shed light on overlapping pathogenic mechanismsthat may unite disparate mutations under a common umbrellaand direct the search for disease-modifying therapies. We havelearned much since the discovery of C9-linked ALS-FTD. Thenext decade promises to illuminate many new aspects of theseoverlapping neurodegenerative diseases. Building on multi-disciplinary efforts of international consortia such as ProjectMinE (www.projectmine.com), GENFI (http://genfi.org.uk/)and RiMOD-FTD (https://www.neurodegenerationresearch.eu/initiatives/annual-calls-for-proposals/closed-calls/risk-factors-2012/risk-factor-call-results/rimod-ftd/), we may begin to fullyresolve ALS-FTD genetic architecture and understand whyindividuals carrying a particular variant go on to develop ALS,FTD, or ALS-FTD.AUTHOR CONTRIBUTIONSFC wrote the first draft. AR and HH critically reviewed the finalversion of this editorial. All authors approved the final version ofthis editorial.REFERENCESBrenner, D., Yilmaz, R., Müller, K., Grehl, T., Petri, S., Meyer, T., et al.(2018). Hot-spot KIF5A mutations cause familial ALS. Brain 141, 688–697.doi: 10.1093/brain/awx370Chia, R., Chiò A., and Traynor, B. J. (2018). Novel genes associated withamyotrophic lateral sclerosis: diagnostic and clinical implications. LancetNeurol. 17, 94–102. doi: 10.1016/S1474-4422(17)30401-5Conforti, F. L., Spataro, R., Sproviero, W., Mazzei, R., Cavalcanti, F.,Condino, F., et al. (2012). Ataxin-1 and ataxin-2 intermediate-lengthPolyQ expansions in amyotrophic lateral sclerosis. Neurology 79, 2315–2320.doi: 10.1212/WNL.0b013e318278b618DeJesus-Hernandez, M., Mackenzie, I. R., Boeve, B. F., Boxer, A. L., Baker, M.,Rutherford, N. J., et al. (2011). Expanded GGGGCC hexanucleotide repeat innoncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS.Neuron 72, 245–256. doi: 10.1016/j.neuron.2011.09.011Elden, A. C., Kim, H. J., Hart, M. P., Chen-Plotkin, A. S., Johnson, B.S., Fang, X., et al. (2010). Ataxin-2 intermediate-length polyglutamineexpansions are associated with increased risk for ALS. Nature 466, 1069–1075.doi: 10.1038/nature09320Guerreiro, R., Gibbons, E., Tábuas-Pereira, M., Kun-Rodrigues, C., Santo, G.C., and Bras, J. (2020). Genetic architecture of common non-Alzheimer’sdisease dementias. Neurobiol. Dis. 142:104946. doi: 10.1016/j.nbd.2020.104946Frontiers in Neuroscience | www.frontiersin.org 2 April 2021 | Volume 15 | Article 680185Conforti et al. Editorial: Multifaceted Genes in ALS-FTDNicolas, A., Kenna, K. P., Renton, A. E., Ticozzi, N., Faghri, F., Chia, R., et al.(2018). Genome-wide analyses identify KIF5A as a novel ALS gene. Neuron 97,1268–1283.e6. doi: 10.1016/j.neuron.2018.02.027Renton, A. E., Majounie, E., Waite, A., Simón-Sánchez, J.,Rollinson, S., Gibbs, J. R., et al. (2011). A hexanucleotide repeatexpansion in C9ORF72 is the cause of chromosome 9p21-linkedALS-FTD. Neuron. 72, 257–268. doi: 10.1016/j.neuron.2011.09.010Rosen, D. R., Siddique, T., Patterson, D., Figlewicz, D. A., Sapp, P., Hentati, A.,et al. (1993).Mutations in Cu/Zn superoxide dismutase gene are associated withfamilial amyotrophic lateral sclerosis. Nature 36, 259–262. doi: 10.1038/362059a0Tazelaar, G. H. P., Boeynaems, S., De Decker, M., van Vugt, J. J. F. A., Kool,L., Goedee, H. S., et al. (2020). ATXN1 repeat expansions confer risk foramyotrophic lateral sclerosis and contribute to TDP-43 mislocalization. BrainCommun. 2:fcaa064. doi: 10.1093/braincomms/fcaa064Conflict of Interest: The authors declare that the research was conducted in theabsence of any commercial or financial relationships that could be construed as apotential conflict of interest.Copyright © 2021 Conforti, Renton and Houlden. This is an open-access articledistributed under the terms of the Creative Commons Attribution License (CC BY).The use, distribution or reproduction in other forums is permitted, provided theoriginal author(s) and the copyright owner(s) are credited and that the originalpublication in this journal is cited, in accordance with accepted academic practice.No use, distribution or reproduction is permitted which does not comply with theseterms.Frontiers in Neuroscience | www.frontiersin.org 3 April 2021 | Volume 15 | Article 680185

Editorial: Multifaceted Genes in Amyotrophic Lateral Sclerosis-Frontotemporal Dementia

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Editorial: Multifaceted Genes in Amyotrophic Lateral Sclerosis-Frontotemporal Dementia

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