Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia
Open accessAbstract
Amyotrophic lateral sclerosis (ALS) is a genetically heterogeneous neurodegenerative syndrome hallmarked by adult-onset loss of motor neurons. We performed exome sequencing of 252 familial ALS (fALS) and 827 control individuals. Gene-based rare variant analysis identified an exome-wide significant enrichment of eight loss-of-function (LoF) mutations in TBK1 (encoding TANK-binding kinase 1) in 13 fALS pedigrees. No enrichment of LoF mutations was observed in a targeted mutation screen of 1,010 sporadic ALS and 650 additional control individuals. Linkage analysis in four families gave an aggregate LOD score of 4.6. In vitro experiments confirmed the loss of expression of TBK1 LoF mutant alleles, or loss of interaction of the C-terminal TBK1 coiled-coil domain (CCD2) mutants with the TBK1 adaptor protein optineurin, which has been shown to be involved in ALS pathogenesis. We conclude that haploinsufficiency of TBK1 causes ALS and fronto-temporal dementia.
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Neuropathological analysis of CNS tissue from ALS patients with TBK1 mutations shows SQSTM1- and TARDBP-positive inclusions in motor neurons and glia, along with reduced TBK1 mRNA and protein, suggesting haploinsufficiency mechanisms.
“Neuropathological analysis of CNS tissue from ALS patients with TBK1 mutations shows SQSTM1- and TARDBP-positive inclusions in motor neurons and glia [206,210,211], along with reduced TBK1 mRNA and protein, suggesting haploinsufficiency mechanisms [205,206].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [206]
TBK1 mutations are responsible for ~1% of patients with familial or otherwise sporadic ALS.
“Whole exome sequencing studies revealed that mutations in TBK1 are also responsible for ~1% of patients with familial or otherwise sporadic ALS [205,206].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [206]
Most ALS-associated TBK1 mutations affect the kinase and the coiled-coiled domains, both of which are vital for TBK1 function.
“Consistent with this, most ALS-associated TBK1 mutations affect the kinase and the coiled-coiled domains, both of which are vital for TBK1 function [206].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [206]
ALS-associated mutations in TBK1, OPTN, SQSTM1, and VCP all affect autophagy as well as microglial function and innate immunity.
“ALS-associated mutations in TBK1, OPTN, SQSTM1, and VCP all affect autophagy as well as microglial function and innate immunity [192,205,206,441–443].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [206]
Mutations in TBK1 are associated with developing FTD.
“Additionally, mutations in TBK1 are associated with developing FTD,317,318”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [318]
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Cites
Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method
Livak, K. J., & Schmittgen, T. D. (2001) · Methods · doi:10.1006/meth.2001.1262 · Cited by 180,860 · see citing works
PLINK: a tool set for whole-genome association and population-based linkage analyses.
Purcell, S., Neale, B., Todd-Brown, K., Thomas, L., Ferreira, M. A. R., Bender, D., Maller, J., Sklar, P., de Bakker, P. I. W., Daly, M. J., et al. (2007) · The American Journal of Human Genetics · doi:10.1086/519795 · Cited by 34,089 · see citing works
<i>Coot</i> : model-building tools for molecular graphics
Emsley, P., & Cowtan, K. (2004) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444904019158 · Cited by 30,571 · see citing works
Repertoires of Autophagy in the Pathogenesis of Ocular Diseases
Li, Y., Jiang, Q. L., Cao, G.-F., Yao, J., & Yan, B. (2015) · Cellular Physiology and Biochemistry · doi:10.1159/000373980 · Cited by 16,351 · see citing works
Haploview: analysis and visualization of LD and haplotype maps
Barrett, J., Fry, B., Maller, J., & Daly, M. (2005) · Bioinform. · doi:10.1093/bioinformatics/bth457 · Cited by 15,086 · see citing works
Mutation of the mouse klotho gene leads to a syndrome resembling ageing
Kuro-o, M., Matsumura, Y., Aizawa, H., Kawaguchi, H., Suga, T., Utsugi, T., Ohyama, Y., Kurabayashi, M., Kaname, T., Kume, E., et al. (1997) · Nature · doi:10.1038/36285 · Cited by 3,837 · see citing works
Merlin—rapid analysis of dense genetic maps using sparse gene flow trees
Abecasis, G. R., Cherny, S. S., Cookson, W., & Cardon, L. R. (2001) · Nature Genetics · doi:10.1038/ng786 · Cited by 3,323 · see citing works
Li, B., & Leal, S. M. (2008) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2008.06.024 · Cited by 1,527 · see citing works
Phosphorylation of the Autophagy Receptor Optineurin Restricts <i>Salmonella</i> Growth
Wild, P., Farhan, H., McEwan, D. G., Wagner, S., Rogov, V. V., Brady, N. R., Richter, B., Korac, J., Waidmann, O., Choudhary, C., et al. (2011) · Science · doi:10.1126/science.1205405 · Cited by 1,298 · see citing works
Self-citationMutations 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 · see citing works
The EFNS Task Force on Diagnosis and Management of Amyotrophic Lateral Sclerosis:, Andersen, P. M., Abrahams, S., Borasio, G. D., de Carvalho, M., Chio, A., Van Damme, P., Hardiman, O., Kollewe, K., Morrison, K. E., et al. (2012) · European Journal of Neurology · doi:10.1111/j.1468-1331.2011.03501.x · Cited by 1,117 · see citing works
Self-citationExome 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 · see citing works
Toward better understanding of artifacts in variant calling from high-coverage samples
Li, H. (2014) · Bioinformatics · doi:10.1093/bioinformatics/btu356 · Cited by 896 · see citing works
Wong, Y. C., & Holzbaur, E. L. F. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1405752111 · Cited by 812 · see citing works
Clinical genetics of amyotrophic lateral sclerosis: what do we really know?
Andersen, P. M., & Al-Chalabi, A. (2011) · Nature Reviews Neurology · doi:10.1038/nrneurol.2011.150 · Cited by 687 · see citing works
Self-citationTBK-1 Promotes Autophagy-Mediated Antimicrobial Defense by Controlling Autophagosome Maturation
Pilli, M., Arko-Mensah, J., Ponpuak, M., Roberts, E., Master, S., Mandell, M. A., Dupont, N., Ornatowski, W., Jiang, S., Bradfute, S. B., et al. (2012) · Immunity · doi:10.1016/j.immuni.2012.04.015 · Cited by 655 · see citing works
Fecto, F. (2011) · Archives of Neurology · doi:10.1001/archneurol.2011.250 · Cited by 650 · see citing works
NF‐κB activation by a signaling complex containing TRAF2, TANK and TBK1, a novel IKK‐related kinase
Pomerantz, J. L., & Baltimore, D. (1999) · The EMBO Journal · doi:10.1093/emboj/18.23.6694 · Cited by 595 · see citing works
Evidence for an oligogenic basis of amyotrophic lateral sclerosis
van Blitterswijk, M., van Es, M. A., Hennekam, E. A. M., Dooijes, D., van Rheenen, W., Medic, J., Bourque, P. R., Schelhaas, H. J., van der Kooi, A. J., de Visser, M., et al. (2012) · Human Molecular Genetics · doi:10.1093/hmg/dds199 · Cited by 338 · see citing works
Ubiquitin-independent function of optineurin in autophagic clearance of protein aggregates
Korac, J., Schaeffer, V., Kovacevic, I., Clement, A. M., Jungblut, B., Behl, C., Terzic, J., & Dikic, I. (2013) · Journal of Cell Science · doi:10.1242/jcs.114926 · Cited by 336 · see citing works
Self-citationAndersen, P. M. (1997) · Brain · doi:10.1093/brain/120.10.1723 · Cited by 301 · see citing works
Self-citationp62/SQSTM1/A170: Physiology and pathology
Komatsu, M., Kageyama, S., & Ichimura, Y. (2012) · Pharmacological Research · doi:10.1016/j.phrs.2012.07.004 · Cited by 301 · see citing works
Dysfunctional nitric oxide signalling increases risk of myocardial infarction
CARDIoGRAM, Erdmann, J., Stark, K. J., Esslinger, U. B., Rumpf, P. M., Koesling, D., de Wit, C., Kaiser, F. J., Braunholz, D., Medack, A., et al. (2013) · Nature · doi:10.1038/nature12722 · Cited by 287 · see citing works
Self-citationOrre, M., Kamphuis, W., Osborn, L. M., Melief, J., Kooijman, L., Huitinga, I., Klooster, J., Bossers, K., & Hol, E. M. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.07.008 · Cited by 269 · see citing works
Crystal Structure and Mechanism of Activation of TANK-Binding Kinase 1
Larabi, A., Devos, J. M., Ng, S., Nanao, M., Round, A. R., Maniatis, T., & Panne, D. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.01.034 · Cited by 251 · see citing works
Copy number variations on chromosome 12q14 in patients with normal tension glaucoma
Fingert, J. H., Robin, A. L., Stone, J. L., Roos, B. R., Davis, L. K., Scheetz, T. E., Bennett, S. R., Wassink, T. H., Kwon, Y. H., Alward, W. L. M., et al. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr123 · Cited by 221 · see citing works
Morton, S., Hesson, L. B., Peggie, M. W., & Cohen, P. (2008) · FEBS Letters · doi:10.1016/j.febslet.2008.02.047 · Cited by 180 · see citing works
TBK1 Mediates Crosstalk Between the Innate Immune Response and Autophagy
Weidberg, H., & Elazar, Z. (2011) · Science Signaling · doi:10.1126/scisignal.2002355 · Cited by 148 · see citing works
Amyotrophic Lateral Sclerosis in South-East England: A Population-Based Study
Abhinav, K., Stanton, B. R., Johnston, C. A., Hardstaff, J. L., Orrell, R. W., Howard, R., Clarke, J., Sakel, M., Ampong, M. A., Shaw, C. E., et al. (2007) · Neuroepidemiology · doi:10.1159/000108917 · Cited by 143 · see citing works
Functional Dissection of the TBK1 Molecular Network
Goncalves, A., Bürckstümmer, T., Dixit, E., Scheicher, R., Górna, M. W., Karayel, E., Sugar, C., Stukalov, A., Berg, T., Kralovics, R., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0023971 · Cited by 136 · see citing works
Akimoto, C., Volk, A. E., van Blitterswijk, M., den Broeck, M. V., Leblond, C. S., Lumbroso, S., Camu, W., Neitzel, B., Onodera, O., van Rheenen, W., et al. (2014) · Journal of Medical Genetics · doi:10.1136/jmedgenet-2014-102360 · Cited by 131 · see citing works
Self-citationInvolvement of the ubiquitin‐like domain of TBK1/IKK‐i kinases in regulation of IFN‐inducible genes
Ikeda, F., Hecker, C., Rozenknop, A., Nordmeier, R. D., Rogov, V. V., Hofmann, K., Akira, S., Dötsch, V., & Đikić, I. (2007) · The EMBO Journal · doi:10.1038/sj.emboj.7601773 · Cited by 121 · see citing works
Hübers, A., Marroquin, N., Schmoll, B., Vielhaber, S., Just, M., Mayer, B., Högel, J., Dorst, J., Mertens, T., Just, W., et al. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.11.034 · Cited by 69 · see citing works
Self-citationUenal, H., Rosenbohm, A., Kufeldt, J., Weydt, P., Goder, K., Ludolph, A., Rothenbacher, D., Nagel, G., & and the ALS registry Study Group (2014) · PLoS ONE · doi:10.1371/journal.pone.0093932 · Cited by 64 · see citing works
Self-citationMotor neuron disease and dementia reported among 13 members of a single family
Gunnarsson, L., Dahlbom, K., & Strandman, E. (1991) · Acta Neurologica Scandinavica · doi:10.1111/j.1600-0404.1991.tb04983.x · Cited by 53 · see citing works
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Sorted by citations
Analysis of protein-coding genetic variation in 60,706 humans
Exome Aggregation Consortium, Lek, M., Karczewski, K. J., Minikel, E. V., Samocha, K. E., Banks, E., Fennell, T., O’Donnell-Luria, A. H., Ware, J. S., Hill, A. J., et al. (2016) · Nature · doi:10.1038/nature19057 · Cited by 9,587 · see citing works
Mechanism and medical implications of mammalian autophagy
Dikic, I., & Elazar, Z. (2018) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-018-0003-4 · Cited by 2,771 · see citing works
Brown, R. H., & Al‐Chalabi, A. (2017) · New England Journal of Medicine · doi:10.1056/nejmra1603471 · Cited by 2,472 · see citing works
Decoding ALS: from genes to mechanism
Taylor, J. P., Brown, R. H., & Cleveland, D. W. (2016) · Nature · doi:10.1038/nature20413 · Cited by 2,047 · see citing works
Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets
Gao, C., Jiang, J., Tan, Y., & Chen, S. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01588-0 · Cited by 1,616 · see citing works
Molecular mechanisms and physiological functions of mitophagy
Onishi, M., Yamano, K., Sato, M., Matsuda, N., & Okamoto, K. (2021) · The EMBO Journal · doi:10.15252/embj.2020104705 · Cited by 1,429 · see citing works
Amyotrophic lateral sclerosis: a clinical review
Masrori, P., & Damme, P. V. (2020) · European Journal of Neurology · doi:10.1111/ene.14393 · Cited by 1,228 · see citing works
Proteasomal and Autophagic Degradation Systems
Đikić, I. (2017) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-061516-044908 · Cited by 1,165 · see citing works
Autophagy and Neurodegeneration: Pathogenic Mechanisms and Therapeutic Opportunities
Menzies, F. M., Fleming, A., Caricasole, A., Bento, C. F., Andrews, S. P., Ashkenazi, A., Füllgrabe, J., Jackson, A., Jimenez Sanchez, M., Karabiyik, C., et al. (2017) · Neuron · doi:10.1016/j.neuron.2017.01.022 · Cited by 1,134 · see citing works
TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS
Yu, C.-H., Davidson, S., Harapas, C. R., Hilton, J. B., Mlodzianoski, M. J., Laohamonthonkul, P., Louis, C., Low, R. R. J., Moecking, J., De Nardo, D., et al. (2020) · Cell · doi:10.1016/j.cell.2020.09.020 · Cited by 1,019 · see citing works
Heo, J.-M., Ordureau, A., Paulo, J. A., Rinehart, J., & Harper, J. W. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.08.016 · Cited by 906 · see citing works
Strong, M. J., Abrahams, S., Goldstein, L. H., Woolley, S., Mclaughlin, P., Snowden, J., Mioshi, E., Roberts-South, A., Benatar, M., HortobáGyi, T., et al. (2017) · Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration · doi:10.1080/21678421.2016.1267768 · Cited by 909 · see citing works
Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles
Galluzzi, L., Bravo-San Pedro, J. M., Levine, B., Green, D. R., & Kroemer, G. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2017.22 · Cited by 842 · see citing works
Stress granules and neurodegeneration
Wolozin, B. L., & Ivanov, P. V. (2019) · Nature reviews. Neuroscience · doi:10.1038/s41583-019-0222-5 · Cited by 782 · see citing works
Autophagy as a promoter of longevity: insights from model organisms
Hansen, M., Rubinsztein, D. C., & Walker, D. W. (2018) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-018-0033-y · Cited by 754 · see citing works
Richter, B., Sliter, D. A., Herhaus, L., Stolz, A., Wang, C., Beli, P., Zaffagnini, G., Wild, P., Martens, S., Wagner, S. A., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1523926113 · Cited by 755 · see citing works
Self-citationC9orf72-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 · see citing works
ALS Genetics, Mechanisms, and Therapeutics: Where Are We Now?
Mejzini, R., Flynn, L. L., Pitout, I. L., Fletcher, S., Wilton, S. D., & Akkari, P. A. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.01310 · Cited by 755 · see citing works
Deciphering the Molecular Signals of PINK1/Parkin Mitophagy
Nguyen, T. N., Padman, B. S., & Lazarou, M. (2016) · Trends in Cell Biology · doi:10.1016/j.tcb.2016.05.008 · Cited by 732 · see citing works
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 673 · see citing works
Genome-Wide Analyses Identify KIF5A as a Novel ALS Gene
Nicolas, A., Kenna, K. P., Renton, A. E., Ticozzi, N., Faghri, F., Chia, R., Dominov, J. A., Kenna, B., Nalls, M. A., Keagle, P. J., et al. (2018) · Neuron · doi:10.1016/j.neuron.2018.02.027 · Cited by 670 · see citing works
Building and decoding ubiquitin chains for mitophagy
Harper, J. W., Ordureau, A., & Heo, J. (2018) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2017.129 · Cited by 668 · see citing works
Mackenzie, I. R., Nicholson, A. M., Sarkar, M., Messing, J. A., Purice, M. D., Pottier, C. P., Annu, K., Baker, M. C., Perkerson, R. B., Kurti, A., et al. (2017) · Neuron · doi:10.1016/j.neuron.2017.07.025 · Cited by 642 · see citing works
Novel genes associated with amyotrophic lateral sclerosis: diagnostic and clinical implications
Chia, R., Chiò, A., & Traynor, B. J. (2017) · The Lancet Neurology · doi:10.1016/s1474-4422(17)30401-5 · Cited by 576 · see citing works
PARALS Registry, van Rheenen, W., SLALOM Group, SLAP Registry, NNIPPS Study Group, Shatunov, A., Dekker, A. M., McLaughlin, R. L., Diekstra, F. P., Pulit, S. L., et al. (2016) · Nature Genetics · doi:10.1038/ng.3622 · Cited by 574 · see citing works
Self-citationThe role of mitochondria in amyotrophic lateral sclerosis
Smith, E. F., Shaw, P. J., & Vos, K. J. D. (2017) · Neuroscience Letters · doi:10.1016/j.neulet.2017.06.052 · Cited by 556 · see citing works
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 · see citing works
Self-citation<i>C9orf72</i> is required for proper macrophage and microglial function in mice
O’Rourke, J. G., Bogdanik, L., Yáñez, A., Lall, D., Wolf, A. J., Muhammad, A. K. M. G., Ho, R., Carmona, S., Vit, J. P., Zarrow, J., et al. (2016) · Science · doi:10.1126/science.aaf1064 · Cited by 550 · see citing works
Mead, R. J., Shan, N., Reiser, H. J., Marshall, F., & Shaw, P. J. (2023) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00612-2 · Cited by 505 · see citing works
Receptor-interacting protein kinase 1 (RIPK1) as a therapeutic target
Mifflin, L., Ofengeim, D., & Yuan, J. (2020) · Nature Reviews Drug Discovery · doi:10.1038/s41573-020-0071-y · Cited by 491 · see citing works
PINK1/PARKIN signalling in neurodegeneration and neuroinflammation
Quinn, P. M. J., Moreira, P. I., Ambrósio, A. F., & Alves, C. H. (2020) · Acta Neuropathologica Communications · doi:10.1186/s40478-020-01062-w · Cited by 486 · see citing works
Cellular functions of cGAS-STING signaling
Chen, C., & Xu, P. (2022) · Trends in Cell Biology · doi:10.1016/j.tcb.2022.11.001 · Cited by 469 · see citing works
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 456 · see citing works
Yao, R.-Q., Ren, C., Xia, Z.-F., & Yao, Y.-M. (2021) · Autophagy · doi:10.1080/15548627.2020.1725377 · Cited by 441 · see citing works
Sellier, C., Campanari, M., Julie Corbier, C., Gaucherot, A., Kolb‐Cheynel, I., Oulad‐Abdelghani, M., Ruffenach, F., Page, A., Ciura, S., Kabashi, E., et al. (2016) · The EMBO Journal · doi:10.15252/embj.201593350 · Cited by 414 · see citing works
Olney, N. T., Spina, S., & Miller, B. L. (2017) · Neurologic Clinics · doi:10.1016/j.ncl.2017.01.008 · Cited by 419 · see citing works
A clinicopathological approach to the diagnosis of dementia
Elahi, F. M., & Miller, B. L. (2017) · Nature Reviews Neurology · doi:10.1038/nrneurol.2017.96 · Cited by 407 · see citing works
Targeting RIPK1 for the treatment of human diseases
Degterev, A., Ofengeim, D., & Yuan, J. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1901179116 · Cited by 411 · see citing works
ALS Genetics: Gains, Losses, and Implications for Future Therapies
Kim, G., Gautier, O., Tassoni-Tsuchida, E., Ma, X. R., & Gitler, A. D. (2020) · Neuron · doi:10.1016/j.neuron.2020.08.022 · Cited by 370 · see citing works
Immune dysregulation in amyotrophic lateral sclerosis: mechanisms and emerging therapies
Beers, D. R., & Appel, S. H. (2019) · The Lancet Neurology · doi:10.1016/s1474-4422(18)30394-6 · Cited by 387 · see citing works
PINK1/Parkin-mediated mitophagy in neurodegenerative diseases
Li, J., Yang, D., Li, Z., Zhao, M., Wang, D., Sun, Z., Wen, P., Dai, Y., Gou, F., Ji, Y., et al. (2022) · Ageing Research Reviews · doi:10.1016/j.arr.2022.101817 · Cited by 388 · see citing works
Mackenzie, I. R., & Neumann, M. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13588 · Cited by 374 · see citing works
Selective autophagy as a potential therapeutic target for neurodegenerative disorders
Scrivo, A., Bourdenx, M., Pampliega, O., & Cuervo, A. M. (2018) · The Lancet Neurology · doi:10.1016/s1474-4422(18)30238-2 · Cited by 355 · see citing works
Moore, A. S., & Holzbaur, E. L. F. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1523810113 · Cited by 351 · see citing works
TBK1: a new player in ALS linking autophagy and neuroinflammation
Oakes, J. A., Davies, M. C., & Collins, M. O. (2017) · Molecular Brain · doi:10.1186/s13041-017-0287-x · Cited by 319 · see citing works
Stavoe, A. K. H., & Holzbaur, E. L. F. (2019) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-100818-125242 · Cited by 328 · see citing works
Inflammation in ALS/FTD pathogenesis
McCauley, M. E., & Baloh, R. H. (2019) · Acta Neuropathologica · doi:10.1007/s00401-018-1933-9 · Cited by 316 · see citing works
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Oskarsson, B., Gendron, T. F., & Staff, N. P. (2018) · Mayo Clinic Proceedings · doi:10.1016/j.mayocp.2018.04.007 · Cited by 315 · see citing works
Pottier, C., Bieniek, K. F., Finch, N., van de Vorst, M., Baker, M., Perkersen, R., Brown, P., Ravenscroft, T., van Blitterswijk, M., Nicholson, A. M., et al. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1436-x · Cited by 312 · see citing works
The identity and function of microglia in neurodegeneration
Song, W. M., & Colonna, M. (2018) · Nature Immunology · doi:10.1038/s41590-018-0212-1 · Cited by 308 · see citing works
ALS Genes in the Genomic Era and their Implications for FTD
Nguyen, H. P., Broeckhoven, C. V., & van der Zee, J. (2018) · Trends in Genetics · doi:10.1016/j.tig.2018.03.001 · Cited by 308 · see citing works
Neuroinflammation in frontotemporal dementia
Bright, F., Werry, E. L., Dobson-Stone, C., Piguet, O., Ittner, L. M., Halliday, G. M., Hodges, J. R., Kiernan, M. C., Loy, C. T., Kassiou, M., et al. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0231-z · Cited by 280 · see citing works
Gene discovery in amyotrophic lateral sclerosis: implications for clinical management
Al-Chalabi, A., van den Berg, L. H., & Veldink, J. (2017) · Nature Reviews Neurology · doi:10.1038/nrneurol.2016.182 · Cited by 287 · see citing works
Bailey, J. N. C., Loomis, S. J., Kang, J. H., Allingham, R. R., Gharahkhani, P., Khor, C. C., Burdon, K. P., Aschard, H., Chasman, D. I., Igo, R. P., et al. (2016) · Nature Genetics · doi:10.1038/ng.3482 · Cited by 273 · see citing works
TDP-43 gains function due to perturbed autoregulation in a Tardbp knock-in mouse model of ALS-FTD
White, M. A., Kim, E., Duffy, A., Adalbert, R., Phillips, B. U., Peters, O. M., Stephenson, J., Yang, S., Massenzio, F., Lin, Z., et al. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0113-5 · Cited by 267 · see citing works
Mitophagy in Alzheimer’s Disease and Other Age-Related Neurodegenerative Diseases
Cai, Q., & Jeong, Y. Y. (2020) · Cells · doi:10.3390/cells9010150 · Cited by 263 · see citing works
Genetics of Amyotrophic Lateral SclerosisPreprint
Ghasemi, M., & Brown, R. H. (2017) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a024125 · Cited by 267 · see citing works
Smith, B. N., Topp, S. D., Fallini, C., Shibata, H., Chen, H.-J., Troakes, C., King, A., Ticozzi, N., Kenna, K. P., Gkazi, S. A., et al. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aad9157 · Cited by 249 · see citing works
The overlapping genetics of amyotrophic lateral sclerosis and frontotemporal dementia
Abramzon, Y. A., Fratta, P., Traynor, B. J., & Chia, R. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00042 · Cited by 244 · see citing works
The Dual Role of Microglia in ALS: Mechanisms and Therapeutic Approaches
Geloso, M. C., Corvino, V., Marchese, E., Serrano, A., Michetti, F., & D’Ambrosi, N. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00242 · Cited by 239 · see citing works
Amyotrophic lateral sclerosis: translating genetic discoveries into therapies
Akçimen, F., Lopez, E. R., Landers, J. E., Nath, A., Chiò, A., Chia, R., & Traynor, B. J. (2023) · Nature Reviews Genetics · doi:10.1038/s41576-023-00592-y · Cited by 234 · see citing works
Root, J. T., Merino, P., Nuckols, A., Johnson, M. A., & Kukar, T. L. (2021) · Neurobiology of Disease · doi:10.1016/j.nbd.2021.105360 · Cited by 230 · see citing works
Autophagy Receptors and Neurodegenerative Diseases
Deng, Z., Purtell, K., Lachance, V., Wold, M. S., Chen, S., & Yue, Z. (2017) · Trends in Cell Biology · doi:10.1016/j.tcb.2017.01.001 · Cited by 239 · see citing works
Autophagy Induction as a Therapeutic Strategy for Neurodegenerative Diseases
Djajadikerta, A., Keshri, S., Tanasa, M. P., Prestil, R., Ryan, L., & Rubinsztein, D. C. (2019) · Journal of Molecular Biology · doi:10.1016/j.jmb.2019.12.035 · Cited by 238 · see citing works
Detection and Clearance of Damaged Lysosomes by the Endo-Lysosomal Damage Response and Lysophagy
Papadopoulos, C., & Meyer, H. (2017) · Current Biology · doi:10.1016/j.cub.2017.11.012 · Cited by 230 · see citing works
Expanding the ubiquitin code through post‐translational modification
Herhaus, L., & Đikić, I. (2015) · EMBO Reports · doi:10.15252/embr.201540891 · Cited by 230 · see citing works
Autophagy in the eye: Development, degeneration, and aging
Boya, P., Esteban‐Martínez, L., Serrano‐Puebla, A., Gómez‐Sintes, R., & Villarejo‐Zori, B. (2016) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2016.08.001 · Cited by 231 · see citing works
Deng, Z., Lim, J., Wang, Q., Purtell, K., Wu, S., Palomo, G. M., Tan, H., Manfredi, G., Zhao, Y., Peng, J., et al. (2019) · Autophagy · doi:10.1080/15548627.2019.1644076 · Cited by 232 · see citing works
Evolving and Expanding the Roles of Mitophagy as a Homeostatic and Pathogenic Process
Gustafsson, Å. B., & Dorn, G. W. (2018) · Physiological Reviews · doi:10.1152/physrev.00005.2018 · Cited by 229 · see citing works
Hot-spot KIF5A mutations cause familial ALS
Brenner, D., Yilmaz, R., Müller, K., Grehl, T., Petri, S., Meyer, T., Großkreutz, J., Weydt, P., Ruf, W. P., Neuwirth, C., et al. (2017) · Brain · doi:10.1093/brain/awx370 · Cited by 228 · see citing works
Self-citationHuman TBK1: A Gatekeeper of Neuroinflammation
Ahmad, L., Zhang, S.-Y., Casanova, J.-L., & Sancho-Shimizu, V. (2016) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2016.04.006 · Cited by 208 · see citing works
Gao, F., Almeida, S., & Lopez‐Gonzalez, R. (2017) · The EMBO Journal · doi:10.15252/embj.201797568 · Cited by 218 · see citing works
Rare-variant collapsing analyses for complex traits: guidelines and applications
Povysil, G., Petrovski, S., Hostyk, J. A., Aggarwal, V. S., Allen, A. S., & Goldstein, D. B. (2019) · Nature Reviews Genetics · doi:10.1038/s41576-019-0177-4 · Cited by 202 · see citing works
Motor Neuron Susceptibility in ALS/FTD
Ragagnin, A., Shadfar, S., Vidal, M., Jamali, M. S., & Atkin, J. D. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00532 · Cited by 216 · see citing works
Mechanisms of Selective Autophagy in Normal Physiology and Cancer
Mancias, J. D., & Kimmelman, A. C. (2016) · Journal of Molecular Biology · doi:10.1016/j.jmb.2016.02.027 · Cited by 196 · see citing works
Modelling amyotrophic lateral sclerosis: progress and possibilities
Damme, P. V., Robberecht, W., & Bosch, L. V. D. (2017) · Disease Models & Mechanisms · doi:10.1242/dmm.029058 · Cited by 203 · see citing works
Therapeutic targeting of autophagy in neurodegenerative and infectious diseases
Rubinsztein, D. C., Bento, C. F., & Deretic, V. (2015) · Journal of Experimental Medicine · doi:10.1084/jem.20150956 · Cited by 202 · see citing works
Bridging biophysics and neurology: aberrant phase transitions in neurodegenerative disease
Nedelsky, N. B., & Taylor, J. P. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0157-5 · Cited by 199 · see citing works
Truban, D., Hou, X., Caulfield, T. R., Fiesel, F. C., & Springer, W. (2016) · Journal of Parkinson’s Disease · doi:10.3233/jpd-160989 · Cited by 237 · see citing works
Autophagy and ALS: mechanistic insights and therapeutic implications
Chua, J. P., De Calbiac, H., Kabashi, E., & Barmada, S. J. (2022) · Autophagy · doi:10.1080/15548627.2021.1926656 · Cited by 189 · see citing works
“SQSTM1- and TARDBP-positive inclusions in motor neurons and glia [206,210,211], along with reduced TBK1 mRNA and protein, suggesting haploinsufficiency mechanisms [205,206].”
BackgroundProteostasis Failure in Neurodegenerative Diseases: Focus on Oxidative Stress
Höhn, A., Tramutola, A., & Cascella, R. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/5497046 · Cited by 197 · see citing works
ALS: A bucket of genes, environment, metabolism and unknown ingredients
Zufiría, M., Gil-Bea, F. J., Fernández‐Torrón, R., Poza, J. J., Muñoz-Blanco, J. L., Rojas‐García, R., Riancho, J., & de Munaín, A. L. (2016) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2016.05.004 · Cited by 192 · see citing works
Association Between Autophagy and Neurodegenerative Diseases
Fujikake, N., Shin, M., & Shimizu, S. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00255 · Cited by 167 · see citing works
Familial Amyotrophic Lateral Sclerosis
Boylan, K. (2015) · Neurologic Clinics · doi:10.1016/j.ncl.2015.07.001 · Cited by 187 · see citing works
Autophagy-Independent Lysosomal Targeting Regulated by ULK1/2-FIP200 and ATG9
Goodwin, J. M., Dowdle, W. E., DeJesus, R., Wang, Z., Bergman, P., Kobylarz, M. J., Lindeman, A., Xavier, R. J., McAllister, G., Nyfeler, B., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.08.034 · Cited by 185 · see citing works
Microglia as Dynamic Cellular Mediators of Brain Function
Wright-Jin, E. C., & Gutmann, D. H. (2019) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2019.08.013 · Cited by 186 · see citing works
Autophagic and endo-lysosomal dysfunction in neurodegenerative disease
Malik, B. R., Maddison, D. C., Smith, G. A., & Peters, O. M. (2019) · Molecular Brain · doi:10.1186/s13041-019-0504-x · Cited by 180 · see citing works
Broce, I., Karch, C. M. M., Wen, N., Fan, C. C., Wang, Y., Tan, C. H., Kouri, N., Ross, O. A., Höglinger, G. U., Müller, U., et al. (2018) · PLoS Medicine · doi:10.1371/journal.pmed.1002487 · Cited by 184 · see citing works
Loss of <i>TBK1</i> is a frequent cause of frontotemporal dementia in a Belgian cohort
Gijselinck, I., Van Mossevelde, S., van der Zee, J., Sieben, A., Philtjens, S., Heeman, B., Engelborghs, S., Vandenbulcke, M., De Baets, G., Bäumer, V., et al. (2015) · Neurology · doi:10.1212/wnl.0000000000002220 · Cited by 174 · see citing works
Autophagy and mitophagy in ALS
Evans, C. S., & Holzbaur, E. L. F. (2018) · Neurobiology of Disease · doi:10.1016/j.nbd.2018.07.005 · Cited by 178 · see citing works
Microglia and C9orf72 in neuroinflammation and ALS and frontotemporal dementia
Lall, D., & Baloh, R. H. (2017) · Journal of Clinical Investigation · doi:10.1172/jci90607 · Cited by 175 · see citing works
The roles of hnRNP A2 / B1 in RNA biology and disease
Liu, Y., & Shi, S. (2020) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.1612 · Cited by 178 · see citing works
Mathur, V., Burai, R., Vest, R. T., Bonanno, L. N., Lehallier, B., Zardeneta, M. E., Mistry, K. N., Do, D., Marsh, S. E., Abud, E. M., et al. (2017) · Neuron · doi:10.1016/j.neuron.2017.11.032 · Cited by 175 · see citing works
The Function of Autophagy in Neurodegenerative Diseases
Kiriyama, Y., & Nochi, H. (2015) · International Journal of Molecular Sciences · doi:10.3390/ijms161125990 · Cited by 168 · see citing works
Targeting mitophagy in neurodegenerative diseases
Antico, O., Thompson, P. W., Hertz, N. T., Muqit, M. M. K., & Parton, L. E. (2025) · Nature Reviews Drug Discovery · doi:10.1038/s41573-024-01105-0 · Cited by 178 · see citing works
Eapen, V. V., Swarup, S., Hoyer, M., Paulo, J. A., & Harper, J. W. (2021) · eLife · doi:10.7554/elife.72328 · Cited by 162 · see citing works
Goode, A., Butler, K., Long, J., Cavey, J., Scott, D., Shaw, B., Sollenberger, J., Gell, C., Johansen, T., Oldham, N. J., et al. (2016) · Autophagy · doi:10.1080/15548627.2016.1170257 · Cited by 153 · see citing works
SOD1 in Amyotrophic Lateral Sclerosis: “Ambivalent” Behavior Connected to the Disease
Pansarasa, O., Bordoni, M., Diamanti, L., Sproviero, D., Gagliardi, S., & Cereda, C. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19051345 · Cited by 160 · see citing works
Ito, Y. A., & Di Polo, A. (2017) · Mitochondrion · doi:10.1016/j.mito.2017.08.014 · Cited by 142 · see citing works
Genetics of <scp>FTLD</scp> : overview and what else we can expect from genetic studies
Pottier, C., Ravenscroft, T. A., Sanchez‐Contreras, M., & Rademakers, R. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13622 · Cited by 148 · see citing works
- Authors
- Freischmidt, A., Wieland, T., Richter, B., Ruf, W., Schaeffer, V., Müller, K., Marroquin, N., Nordin, F., Hübers, A., Weydt, P., Pinto, S., Press, R., Millecamps, S., Molko, N., Bernard, E., Desnuelle, C., Soriani, M.-H., Dorst, J., Graf, E., Nordström, U., Feiler, M. S., Putz, S., Boeckers, T. M., Meyer, T., Winkler, A. S., Winkelman, J., de Carvalho, M., Thal, D. R., Otto, M., Brännström, T., Volk, A. E., Kursula, P., Danzer, K. M., Lichtner, P., Dikic, I., Meitinger, T., Ludolph, A. C., Strom, T. M., Andersen, P. M., & Weishaupt, J. H.
- Affiliations
- Universität Ulm (DE)
- Helmholtz Munich (DE)
- Goethe University Frankfurt (DE)
- Umeå University (SE)
- University of Lisbon (PT)
- Karolinska University Hospital (SE)
- Centre National de la Recherche Scientifique (FR)
- Centre Hospitalier Territorial de Nouvelle-Calédonie (NC)
- Hôpital Pierre Wertheimer (FR)
- Centre Hospitalier Universitaire de Nice (FR)
- Humboldt-Universität zu Berlin (DE)
- Technical University of Munich (DE)
- University of Bergen (NO)
- Corresponding author
- Andersen, Peter M
- Weishaupt, Jochen H
- ORCID
- Freischmidt, Axel
- Wieland, Thomas
- Richter, Benjamin
- Ruf, Wolfgang
- Müller, Kathrin
- Marroquin, Nicolai
- Hübers, Annemarie
- Weydt, Patrick
- Pinto, Susana
- Millecamps, Stéphanie
- Bernard, Emilien
- Desnuelle, Claude
- Dorst, Johannes
- Graf, Elisabeth
- Nordström, Ulrika
- Boeckers, Tobias M
- Meyer, Thomas
- Winkler, Andrea S
- Thal, Dietmar R
- Otto, Markus
- Brännström, Thomas
- Volk, Alexander E
- Kursula, Petri
- Danzer, Karin M
- Lichtner, Peter
- Meitinger, Thomas
- Ludolph, Albert C
- Andersen, Peter M
- Weishaupt, Jochen H
- Venue
- Nature Neuroscience
- Published
- 2015-03-24
- Volume
- 18
- Issue
- 5
- Pages
- 631-636
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- OpenAlex
- W2156054547
- Cited by
- 786
- References
- 35
- Citations by year
- 2026: 29 · 2025: 50 · 2024: 48 · 2023: 47 · 2022: 69 · 2021: 75 · 2020: 100 · 2019: 79 · 2018: 88 · 2017: 78 · 2016: 89 · 2015: 32
- FWCI
- 67.45
- Type
- journal article
- Language
- en
- Open access
- green
- lirias.kuleuven.be
- Licence
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Lirias (KU Leuven) (submittedVersion, other-oa)
- HAL (submittedVersion, other-oa)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- Site cant be reached (submittedVersion)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion)
- Funders
- Brain Research Foundation
- Ulla-Carin Lindquists stiftelse för ALS-forskning
- Bundesministerium für Bildung und Forschung (01GI0704)
- Knut och Alice Wallenbergs Stiftelse
- Vetenskapsrådet
- Fondation Charcot
- Bertil Hållstens Forskningsstiftelse
- Swedish Brain Power
- German Network for Motor Neuron Diseases
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- TBK1, haploinsufficiency, familial ALS, frontotemporal dementia, optineurin, loss-of-function mutations, coiled-coil domain, autophagy, neuroinflammation, neurodegeneration, genetic linkage, motor neuron degeneration
- MeSH terms
- Alleles, Amyotrophic Lateral Sclerosis, Cells, Cultured, DNA Mutational Analysis, Europe, Female, Gene Frequency, Humans, Male, Pedigree, Protein Serine-Threonine Kinases, Sequence Analysis, DNA, Protein Structure, Tertiary, Codon, Nonsense, Genetic Heterogeneity, Cell Cycle Proteins, Mutation, Missense, Membrane Transport Proteins, Transcription Factor TFIIIA, Genome-Wide Association Study, Frontotemporal Dementia, Exome
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