Amyotrophic lateral sclerosis: translating genetic discoveries into therapies

Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis

Rosen, D. R., Siddique, T., Patterson, D., Figlewicz, D. A., Sapp, P., Hentati, A., Donaldson, D., Goto, J., O'Regan, J. P., Deng, H.-X., et al. (1993) · Nature · doi:10.1038/362059a0 · Cited by 7,062

Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis

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Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS

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A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD

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The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019

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An Expanded View of Complex Traits: From Polygenic to Omnigenic

Boyle, E. A., Li, Y. I., & Pritchard, J. K. (2017) · Cell · doi:10.1016/j.cell.2017.05.038 · Cited by 2,851

TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis

Sreedharan, J., Blair, I. P., Tripathi, V. B., Hu, X., Vance, C., Rogelj, B., Ackerley, S., Durnall, J. C., Williams, K. L., Buratti, E., et al. (2008) · Science · doi:10.1126/science.1154584 · Cited by 2,630

Mutations in FUS, an RNA Processing Protein, Cause Familial Amyotrophic Lateral Sclerosis Type 6

Vance, C. A., Rogelj, B., Hortobágyi, T., Vos, K. J. D., Nishimura, A. L., Sreedharan, J., Hu, X., Smith, B. N., Ruddy, D., Wright, P. D., et al. (2009) · Science · doi:10.1126/science.1165942 · Cited by 2,625

Mutations in the FUS/TLS Gene on Chromosome 16 Cause Familial Amyotrophic Lateral Sclerosis

Kwiatkowski, T. J., Bosco, D. A., LeClerc, A. L., Tamrazian, E., Vanderburg, C. R., Russ, C., Davis, A., Gilchrist, J. M., Kasarskis, E. J., Munsat, T. L., et al. (2009) · Science · doi:10.1126/science.1166066 · Cited by 2,624

Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy

Finkel, R. S., Mercuri, E., Darras, B. T., Connolly, A. M., Kuntz, N. L., Kirschner, J., Chiriboga, C. A., Saito, K., Servais, L., Tizzano, E., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1702752 · Cited by 2,337

A Controlled Trial of Riluzole in Amyotrophic Lateral Sclerosis

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Advances in oligonucleotide drug delivery

Roberts, T. C., Langer, R., & Wood, M. J. A. (2020) · Nature Reviews Drug Discovery · doi:10.1038/s41573-020-0075-7 · Cited by 2,121

CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia

Frangoul, H., Altshuler, D., Cappellini, M. D., Chen, Y.-S., Domm, J., Eustace, B. K., Foell, J., de la Fuente, J., Grupp, S., Handgretinger, R., et al. (2021) · New England Journal of Medicine · doi:10.1056/nejmoa2031054 · Cited by 1,962

Amyotrophic Lateral Sclerosis

Rowland, L. P., & Shneider, N. A. (2001) · New England Journal of Medicine · doi:10.1056/nejm200105313442207 · Cited by 1,913

State of play in amyotrophic lateral sclerosis genetics

Renton, A. E., Chiò, A., & Traynor, B. J. (2013) · Nature Neuroscience · doi:10.1038/nn.3584 · Cited by 1,626

TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis

Kabashi, E., Valdmanis, P. N., Dion, P., Spiegelman, D., McConkey, B. J., Velde, C. V., Bouchard, J.-P., Lacomblez, L., Pochigaeva, K., Salachas, F., et al. (2008) · Nature Genetics · doi:10.1038/ng.132 · Cited by 1,544

Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS

Kim, H. J., Kim, N. C., Wang, Y., Scarborough, E. A., Moore, J., Diaz, Z., MacLea, K. S., Freibaum, B. D., Li, S., Molliex, A., et al. (2013) · Nature · doi:10.1038/nature11922 · Cited by 1,478

Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein

Watts, G. D. J., Wymer, J., Kovach, M. J., Mehta, S. G., Mumm, S., Darvish, D., Pestronk, A., Whyte, M. P., & Kimonis, V. E. (2004) · Nature Genetics · doi:10.1038/ng1332 · Cited by 1,391

Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS

Elden, A. C., Kim, H.-J., Hart, M. P., Chen‐Plotkin, A. S., Johnson, B. S., Fang, X., Armakola, M., Geser, F., Greene, R. A., Lu, M. M., et al. (2010) · Nature · doi:10.1038/nature09320 · Cited by 1,361

Mutations of optineurin in amyotrophic lateral sclerosis

Maruyama, H., Morino, H., Ito, H., Izumi, Y., Kato, H., Watanabe, Y., Kinoshita, Y., Kamada, M., Nodera, H., Suzuki, H., et al. (2010) · Nature · doi:10.1038/nature08971 · Cited by 1,265

Exome Sequencing Reveals VCP Mutations as a Cause of Familial ALS

Johnson, J. O., Mandrioli, J., Benatar, M., Abramzon, Y., Van Deerlin, V. M., Trojanowski, J. Q., Gibbs, J. R., Brunetti, M., Gronka, S., Wuu, J., et al. (2010) · Neuron · doi:10.1016/j.neuron.2010.11.036 · Cited by 1,235

Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study

Majounie, E., Renton, A. E., Mok, K., Dopper, E. G., Waite, A., Rollinson, S., Chiò, A., Restagno, G., Nicolaou, N., Simon-Sanchez, J., et al. (2012) · The Lancet Neurology · doi:10.1016/s1474-4422(12)70043-1 · Cited by 1,210

Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia

Deng, H.-X., Chen, W., Hong, S.-T., Boycott, K. M., Gorrie, G. H., Siddique, N., Yang, Y., Fecto, F., Shi, Y., Zhai, H., et al. (2011) · Nature · doi:10.1038/nature10353 · Cited by 1,174

Unconventional Translation of C9ORF72 GGGGCC Expansion Generates Insoluble Polypeptides Specific to c9FTD/ALS

Ash, P. E. A., Bieniek, K. F., Gendron, T. F., Caulfield, T. R., Lin, W.-L., DeJesus‐Hernandez, M., van Blitterswijk, M., Jansen‐West, K. R., Paul, J. W., Rademakers, R., et al. (2013) · Neuron · doi:10.1016/j.neuron.2013.02.004 · Cited by 1,127

Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial

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Mutant dynactin in motor neuron disease

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Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways

Cirulli, E. T., Lasseigne, B. N., Petrovski, S., Sapp, P. C., Dion, P. A., Leblond, C. S., Couthouis, J., Lu, Y.-F., Wang, Q., Krueger, B. J., et al. (2015) · Science · doi:10.1126/science.aaa3650 · Cited by 966

A Mutation in the Vesicle-Trafficking Protein VAPB Causes Late-Onset Spinal Muscular Atrophy and Amyotrophic Lateral Sclerosis

Nishimura, A. L., Mitne-Neto, M., Silva, H. C. A., Richieri-Costa, A., Middleton, S., Cascio, D., Kok, F., Oliveira, J. R. M., Gillingwater, T., Webb, J., et al. (2004) · The American Journal of Human Genetics · doi:10.1086/425287 · Cited by 880

Global Epidemiology of Amyotrophic Lateral Sclerosis: A Systematic Review of the Published Literature

Chiò, A., Logroscino, G., Traynor, B. J., Collins, J., Simeone, J. C., Goldstein, L. A., & White, L. A. (2013) · Neuroepidemiology · doi:10.1159/000351153 · Cited by 862

GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport

Freibaum, B. D., Lu, Y., Lopez-Gonzalez, R., Kim, N. C., Almeida, S., Lee, K.-H., Badders, N., Valentine, M., Miller, B. L., Wong, P. C., et al. (2015) · Nature · doi:10.1038/nature14974 · Cited by 841

Knocking down disease: a progress report on siRNA therapeutics

Wittrup, A., & Lieberman, J. (2015) · Nature Reviews Genetics · doi:10.1038/nrg3978 · Cited by 827

Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia

Skibinski, G., Parkinson, N. J., Brown, J. M., Chakrabarti, L., Lloyd, S. L., Hummerich, H., Nielsen, J. E., Hodges, J. R., Spillantini, M. G., Thusgaard, T., et al. (2005) · Nature Genetics · doi:10.1038/ng1609 · Cited by 822

DNA/RNA Helicase Gene Mutations in a Form of Juvenile Amyotrophic Lateral Sclerosis (ALS4)

Chen, Y.-Z., Bennett, C. L., Huynh, H. M., Blair, I. P., Puls, I., Irobi, J., Dierick, I., Abel, A., Kennerson, M. L., Rabin, B. A., et al. (2004) · The American Journal of Human Genetics · doi:10.1086/421054 · Cited by 809

Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia

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Causes

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The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis

Yang, Y., Hentati, A., Deng, H.-X., Dabbagh, O., Sasaki, T., Hirano, M., Hung, W.-Y., Ouahchi, K., Yan, J., Azim, A. C., et al. (2001) · Nature Genetics · doi:10.1038/ng1001-160 · Cited by 743

C9orf72-mediated ALS and FTD: multiple pathways to disease

Balendra, R., & Isaacs, A. M. (2018) · Nature Reviews Neurology · doi:10.1038/s41582-018-0047-2 · Cited by 715

Targeting Huntingtin Expression in Patients with Huntington’s Disease

Tabrizi, S. J., Leavitt, B. R., Landwehrmeyer, G. B., Wild, E. J., Saft, C., Barker, R. A., Blair, N. F., Craufurd, D., Priller, J., Rickards, H., et al. (2019) · New England Journal of Medicine · doi:10.1056/nejmoa1900907 · Cited by 708

TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD

Ling, J. P., Pletniková, O., Troncoso, J. C., & Wong, P. C. (2015) · Science · doi:10.1126/science.aab0983 · Cited by 697

Genome-Wide Analyses Identify KIF5A as a Novel ALS Gene

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Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS

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<emph type="ital">SQSTM1</emph> Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis

Fecto, F. (2011) · Archives of Neurology · doi:10.1001/archneurol.2011.250 · Cited by 650

Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis

Wu, C.-H., Fallini, C., Ticozzi, N., Keagle, P. J., Sapp, P. C., Piotrowska, K., Lowe, P., Koppers, M., McKenna-Yasek, D. M., Baron, D. M., et al. (2012) · Nature · doi:10.1038/nature11280 · Cited by 624

Novel genes associated with amyotrophic lateral sclerosis: diagnostic and clinical implications

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Dyslipidemia is a protective factor in amyotrophic lateral sclerosis

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Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis

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Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice

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Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons

Shi, Y., Lin, S., Staats, K. A., Li, Y., Chang, W.-H., Hung, S.-T., Hendricks, E., Linares, G. R., Wang, Y., Son, E. Y., et al. (2018) · Nature Medicine · doi:10.1038/nm.4490 · Cited by 566

Controversies and priorities in amyotrophic lateral sclerosis

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Exome Sequencing Links Corticospinal Motor Neuron Disease to Common Neurodegenerative Disorders

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Prion-like Properties of Pathological TDP-43 Aggregates from Diseased Brains

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TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A

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Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

van Rheenen, W., van der Spek, R. A. A., Bakker, M. K., van Vugt, J. J. F. A., Hop, P. J., Zwamborn, R. A. J., de Klein, N., Westra, H.-J., Bakker, O. B., Deelen, P., et al. (2021) · Nature Genetics · doi:10.1038/s41588-021-00973-1 · Cited by 542

A Kinesin Heavy Chain (KIF5A) Mutation in Hereditary Spastic Paraplegia (SPG10)

Reid, E., Kloos, M. T., Ashley‐Koch, A. E., Hughes, L., Bevan, S., Svenson, I. K., Graham, F. L., Gaskell, P. C., Dearlove, A., Pericak‐Vance, M. A., et al. (2002) · The American Journal of Human Genetics · doi:10.1086/344210 · Cited by 540

Genetic epidemiology of amyotrophic lateral sclerosis: a systematic review and meta-analysis

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Mutant FUS proteins that cause amyotrophic lateral sclerosis incorporate into stress granules

Bosco, D. A., Lemay, N., Ko, H. K., Zhou, H., Burke, C., Kwiatkowski, T. J., Sapp, P. C., McKenna-Yasek, D. M., Brown, R. H., & Hayward, L. J. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddq335 · Cited by 537

Epidemiology of mutations in superoxide dismutase in amyotrophic lateal sclerosis

Cudkowicz, M., McKenna‐Yasek, D., Sapp, P. C., Chin, W., Geller, B. A., Hayden, D. L., Schoenfeld, D., Hosler, B. A., Horvitz, H. R., & Brown, R. H. (1997) · Annals of Neurology · doi:10.1002/ana.410410212 · Cited by 533

Projected increase in amyotrophic lateral sclerosis from 2015 to 2040

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A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement

Bannwarth, S., Ait-El-Mkadem, S., Chaussenot, A., Genin, E. C., Lacas‐Gervais, S., Fragaki, K., Berg-Alonso, L., Kageyama, Y., Serre, V., Moore, D. G., et al. (2014) · Brain · doi:10.1093/brain/awu138 · Cited by 507

Silencing mutant SOD1 using RNAi protects against neurodegeneration and extends survival in an ALS model

Ralph, G. S., Radcliffe, P. A., Day, D. M., Carthy, J. M., Leroux, M. A., Lee, D. C. P., Wong, L., Bilsland, L. G., Greensmith, L., Kingsman, S. M., et al. (2005) · Nature Medicine · doi:10.1038/nm1205 · Cited by 507

Antisense oligonucleotide therapy for neurodegenerative disease

Smith, R. A. (2006) · Journal of Clinical Investigation · doi:10.1172/jci25424 · Cited by 506

The role of TDP-43 mislocalization in amyotrophic lateral sclerosis

Suk, T. R., & Rousseaux, M. W. C. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00397-1 · Cited by 483

Human endogenous retrovirus-K contributes to motor neuron disease

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Variants of the heavy neurofilament subunit are associated with the development of amyotrophic lateral sclerosis

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Lentiviral-mediated silencing of SOD1 through RNA interference retards disease onset and progression in a mouse model of ALS

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Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis

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Using genetic data to strengthen causal inference in observational research

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Emerging insights into the complex genetics and pathophysiology of amyotrophic lateral sclerosis

Goutman, S. A., Hardiman, O. M., Al‐Chalabi, A., Chiò, A., Savelieff, M. G., Kiernan, M. C., & Feldman, E. L. (2022) · The Lancet Neurology · doi:10.1016/s1474-4422(21)00414-2 · Cited by 432

Spatiotemporal dynamics of molecular pathology in amyotrophic lateral sclerosis

Maniatis, S., Äijö, T., Vickovic, S., Braine, C., Kang, K., Mollbrink, A., Fagegaltier, D., Andrusivová, Ž., Saarenpää, S., Saiz-Castro, G., et al. (2019) · Science · doi:10.1126/science.aav9776 · Cited by 429

Analysis of amyotrophic lateral sclerosis as a multistep process: a population-based modelling study

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Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis

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ALS phenotypes with mutations in CHMP2B (charged multivesicular body protein 2B)

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Linkage of a Gene Causing Familial Amyotrophic Lateral Sclerosis to Chromosome 21 and Evidence of Genetic-Locus Heterogeneity

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Hereditary Sensory Neuropathy Type 1 Is Caused by the Accumulation of Two Neurotoxic Sphingolipids

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Exome-wide Rare Variant Analysis Identifies TUBA4A Mutations Associated with Familial ALS

Smith, B. N., Ticozzi, N., Fallini, C., Gkazi, S. A., Topp, S. D., Kenna, K. P., Scotter, E. L., Kost, J., Keagle, P. J., Miller, J. W., et al. (2014) · Neuron · doi:10.1016/j.neuron.2014.09.027 · Cited by 368

Targeting mi R‐155 restores abnormal microglia and attenuates disease in SOD 1 mice

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Mutant Huntingtin Disrupts the Nuclear Pore Complex

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