Heterozygous Tbk1 loss has opposing effects in early and late stages of ALS in mice
Open accessAbstract
Heterozygous loss-of-function mutations of TANK-binding kinase 1 (TBK1) cause familial ALS, yet downstream mechanisms of TBK1 mutations remained elusive. TBK1 is a pleiotropic kinase involved in the regulation of selective autophagy and inflammation. We show that heterozygous Tbk1 deletion alone does not lead to signs of motoneuron degeneration or disturbed autophagy in mice during a 200-d observation period. Surprisingly, however, hemizygous deletion of Tbk1 inversely modulates early and late disease phases in mice additionally overexpressing ALS-linked SOD1G93A, which represents a “second hit” that induces both neuroinflammation and proteostatic dysregulation. At the early stage, heterozygous Tbk1 deletion impairs autophagy in motoneurons and prepones both the clinical onset and muscular denervation in SOD1G93A/Tbk1+/− mice. At the late disease stage, however, it significantly alleviates microglial neuroinflammation, decelerates disease progression, and extends survival. Our results indicate a profound effect of TBK1 on brain inflammatory cells under pro-inflammatory conditions and point to a complex, two-edged role of TBK1 in SOD1-linked ALS.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Tbk1 haploinsufficiency impairs motor neuron autophagy and accelerates clinical phenotypes as well as the accumulation of mutant SOD1 in transgenic ALS mouse models.
“Tbk1 haploinsufficiency impairs motor neuron autophagy and accelerates clinical phenotypes as well as the accumulation of mutant SOD1 in transgenic ALS mouse models [214,215].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [214]
In the setting of the SOD1G93A mutation, loss of TBK1 or pathogenic TBK1 mutations accentuate several pathologic features of ALS (disease onset, muscle denervation) while ameliorating others (inflammation, early death).
“in the setting of the SOD1G93A mutation, loss of TBK1 or pathogenic TBK1 mutations accentuate several pathologic features of ALS (disease onset, muscle denervation) while ameliorating others (inflammation, early death) [214].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [214]
Ubiquitous expression of ALS-related TBK1 mutations, heterozygous TBK1 deletion, or motor neuron-specific TBK1 deletion result in loss of function phenotypes but are insufficient to produce ALS-related neurodegeneration in mice.
“Ubiquitous expression of ALS-related TBK1 mutations, heterozygous TBK1 deletion, or motor neuron-specific TBK1 deletion result in loss of function phenotypes but are insufficient to produce ALS-related neurodegeneration in mice [214,215].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [214]
Impaired autophagy sensitizes the nervous system to key pathogenic events occurring early in ALS pathogenesis.
“These findings not only suggest that impaired autophagy sensitizes the nervous system to key pathogenic events occurring early in ALS pathogenesis”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [214]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
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
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
Polazzi, E., Mengoni, I., Caprini, M., Peña‐Altamira, E., Kurtys, E., & Monti, B. (2012) · Neurosignals · doi:10.1159/000337115 · Cited by 9,023 · see citing works
Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice
Hara, T., Nakamura, K., Matsui, M., Yamamoto, A., Nakahara, Y., Suzuki-Migishima, R., Yokoyama, M., Mishima, K., Saito, I., Okano, H., et al. (2006) · Nature · doi:10.1038/nature04724 · Cited by 3,882 · 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
Krasemann, S., Madore, C., Cialic, R., Baufeld, C., Calcagno, N., El Fatimy, R., Beckers, L., O’Loughlin, E., Xu, Y., Fanek, Z., et al. (2017) · Immunity · doi:10.1016/j.immuni.2017.08.008 · Cited by 2,979 · see citing works
Onset and Progression in Inherited ALS Determined by Motor Neurons and Microglia
Boillée, S., Yamanaka, K., Lobsiger, C. S., Copeland, N. G., Jenkins, N. A., Kassiotis, G., Kollias, G., & Cleveland, D. W. (2006) · Science · doi:10.1126/science.1123511 · Cited by 1,623 · see citing works
Self-citationPhosphorylation 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
Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis
Yamanaka, K., Chun, S. J., Boillee, S., Fujimori-Tonou, N., Yamashita, H., Gutmann, D. H., Takahashi, R., Misawa, H., & Cleveland, D. W. (2008) · Nature Neuroscience · doi:10.1038/nn2047 · Cited by 1,140 · see citing works
Self-citationEverts, B., Amiel, E., Huang, S. C.-C., Smith, A. M., Chang, C.-H., Lam, W. Y., Redmann, V., Freitas, T. C., Blagih, J., van der Windt, G. J. W., et al. (2014) · Nature Immunology · doi:10.1038/ni.2833 · Cited by 1,064 · see citing works
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 · see citing works
Type I interferon: friend or foe?
Trinchieri, G. (2010) · The Journal of Experimental Medicine · doi:10.1084/jem.20101664 · Cited by 838 · see citing works
Gene expression markers of Tumor Infiltrating Leukocytes
Danaher, P. J., Warren, S. E., Dennis, L. M., D’Amico, L., White, A. M., Disis, M. L., Geller, M. A., Odunsi, K. O., Beechem, J., & Fling, S. P. (2017) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-017-0215-8 · Cited by 791 · see citing works
Beers, D. R., Henkel, J. S., Xiao, Q., Zhao, W., Wang, J., Yen, A. A., Siklos, L., McKercher, S. R., & Appel, S. H. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0607423103 · Cited by 733 · see citing works
TBK-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
Holtman, I. R., Raj, D. D., Miller, J. A., Schaafsma, W., Yin, Z., Brouwer, N., Wes, P. D., Möller, T., Orre, M., Kamphuis, W., et al. (2015) · Acta Neuropathologica Communications · doi:10.1186/s40478-015-0203-5 · Cited by 619 · see citing works
Hemmi, H., Takeuchi, O., Sato, S., Yamamoto, M., Kaisho, T., Sanjo, H., Kawai, T., Hoshino, K., Takeda, K., & Akira, S. (2004) · The Journal of Experimental Medicine · doi:10.1084/jem.20040520 · Cited by 576 · see citing works
Self-citationTBK1 Suppresses RIPK1-Driven Apoptosis and Inflammation during Development and in Aging
Xu, D., Jin, T., Zhu, H., Chen, H., Ofengeim, D., Zou, C., Mifflin, L., Pan, L., Amin, P., Li, W., et al. (2018) · Cell · doi:10.1016/j.cell.2018.07.041 · Cited by 461 · see citing works
Reilly, S. M., Chiang, S.-H., Decker, S. J., Chang, L. C., Uhm, M., Larsen, M. J., Rubin, J. R., Mowers, J. C., White, N. M. A., Hochberg, I., et al. (2013) · Nature Medicine · doi:10.1038/nm.3082 · Cited by 431 · see citing works
Bonnard, M., Mirtsos, C., Suzuki, S., Graham, K., Huang, J., Ng, M., Itié, A., Wakeham, A., Shahinian, A., Henzel, W. J., et al. (2000) · The EMBO Journal · doi:10.1093/emboj/19.18.4976 · Cited by 381 · 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
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
Rodent Models of Amyotrophic Lateral Sclerosis
Philips, T., & Rothstein, J. D. (2015) · Current Protocols in Pharmacology · doi:10.1002/0471141755.ph0567s69 · Cited by 292 · see citing works
TBK1 at the Crossroads of Inflammation and Energy Homeostasis in Adipose Tissue
Zhao, P., Wong, K. I., Sun, X., Reilly, S. M., Uhm, M., Liao, Z., Skorobogatko, Y. V., & Saltiel, A. R. (2018) · Cell · doi:10.1016/j.cell.2018.01.007 · Cited by 252 · see citing works
Assessing disease onset and progression in the SOD1 mouse model of ALS
Weydt, P., Hong, S. Y., Kliot, M., & Möller, T. (2003) · Neuroreport · doi:10.1097/01.wnr.0000073685.00308.89 · Cited by 227 · see citing works
TBK1 Directly Engages Akt/PKB Survival Signaling to Support Oncogenic Transformation
Ou, Y.-H., Torres, M. J., Ram, R. R., Formstecher, É., Roland, C. L., Cheng, T., Brekken, R. A., Wurz, R. P., Tasker, A. S., Polverino, T., et al. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.01.019 · Cited by 224 · see citing works
Human 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
Rudnick, N. D., Griffey, C. J., Guarnieri, P., Gerbino, V., Wang, X., Piersaint, J. A., Tapia, J. C., Rich, M. M., & Maniatis, T. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1704294114 · Cited by 189 · see citing works
From animal models to human disease: a genetic approach for personalized medicine in ALS
Picher‐Martel, V., Valdmanis, P. N., Gould, P. V., Julien, J., & Dupré, N. (2016) · Acta Neuropathologica Communications · doi:10.1186/s40478-016-0340-5 · Cited by 150 · 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
The kinase TBK1 controls IgA class switching by negatively regulating noncanonical NF-κB signaling
Jin, J., Xiao, Y., Chang, J.-H., Yu, J., Hu, H., Starr, R., Brittain, G. C., Chang, M., Cheng, X., & Sun, S.-C. (2012) · Nature Immunology · doi:10.1038/ni.2423 · Cited by 136 · see citing works
Regulation of T-cell activation and migration by the kinase TBK1 during neuroinflammation
Yu, J., Zhou, X., Chang, M., Nakaya, M., Chang, J.-H., Xiao, Y., William Lindsey, J., Dorta-Estremera, S., Cao, W., Zal, A., et al. (2015) · Nature Communications · doi:10.1038/ncomms7074 · Cited by 118 · see citing works
Wiese, S., Herrmann, T., Drepper, C., Jablonka, S., Funk, N., Klausmeyer, A., Rogers, M., Rush, R. A., & Sendtner, M. (2009) · Nature Protocols · doi:10.1038/nprot.2009.193 · Cited by 118 · see citing works
Self-citationActivation of interferon signaling pathways in spinal cord astrocytes from an ALS mouse model
Wang, R., Yang, B., & Zhang, D. (2011) · Glia · doi:10.1002/glia.21167 · Cited by 115 · see citing works
Pillai, S., Nguyen, J. V., Johnson, J., Haura, E. B., Coppola, D., & Chellappan, S. (2015) · Nature Communications · doi:10.1038/ncomms10072 · Cited by 103 · see citing works
Pathogenic role of BECN1/Beclin 1 in the development of amyotrophic lateral sclerosis
Nassif, M., Valenzuela, V., Rojas-Rivera, D., Vidal, R., Matus, S., Castillo, K., Fuentealba, Y., Kroemer, G., Levine, B., & Hetz, C. (2014) · Autophagy · doi:10.4161/auto.28784 · Cited by 100 · see citing works
Hasan, M., Gonugunta, V. K., Dobbs, N., Ali, A., Palchik, G. A., Calvaruso, M. A., DeBerardinis, R. J., & Yan, N. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1611113114 · Cited by 99 · see citing works
A subcutaneous adipose tissue–liver signalling axis controls hepatic gluconeogenesis
Reilly, S. M., Ahmadian, M., Zamarron, B. F., Chang, L. C., Uhm, M., Poirier, B., Peng, X., Krause, D., Korytnaya, E., Neidert, A., et al. (2015) · Nature Communications · doi:10.1038/ncomms7047 · Cited by 84 · see citing works
Serum microRNAs in sporadic amyotrophic lateral sclerosis
Freischmidt, A., Müller, K., Zondler, L., Weydt, P., Mayer, B., Arnim, C. A. F. V., Hübers, A., Dorst, J., Otto, M., Holzmann, K., et al. (2015) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2015.06.003 · Cited by 83 · see citing works
Self-citationCutting Edge: Inhibiting TBK1 by Compound II Ameliorates Autoimmune Disease in Mice
Hasan, M., Dobbs, N., Khan, S., White, M. A., Wakeland, E. K., Li, Q., & Yan, N. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1500162 · Cited by 76 · see citing works
Fumaric Acid Esters Stimulate Astrocytic VEGF Expression through HIF-1α and Nrf2
Wiesner, D., Merdian, I., Lewerenz, J., Ludolph, A. C., Dupuis, L., & Witting, A. (2013) · PLoS ONE · doi:10.1371/journal.pone.0076670 · Cited by 45 · see citing works
Self-citationLow autophagy capacity implicated in motor system vulnerability to mutant superoxide dismutase
Tokuda, E., Brännström, T., Andersen, P. M., & Marklund, S. L. (2016) · Acta Neuropathologica Communications · doi:10.1186/s40478-016-0274-y · Cited by 41 · see citing works
Möser, C. V., Stephan, H., Altenrath, K., Kynast, K. L., Russe, O. Q., Olbrich, K., Geißlinger, G., & Niederberger, E. (2015) · Journal of Neuroinflammation · doi:10.1186/s12974-015-0319-3 · Cited by 33 · see citing works
Grand, J. N. L., Bon, K., Fraîchard, A., Zhang, J., Jouvenot, M., Risold, P., Boyer‐Guittaut, M., & Delage-Mourroux, R. (2013) · PLoS ONE · doi:10.1371/journal.pone.0063133 · Cited by 29 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
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
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
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
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
“accumulation of mutant SOD1 in transgenic ALS mouse models [214,215].”
BackgroundC9orf72 deficiency promotes microglial-mediated synaptic loss in aging and amyloid accumulation
Lall, D., Lorenzini, I., Mota, T. A., Bell, S., Mahan, T. E., Ulrich, J. D., Davtyan, H., Rexach, J. E., Muhammad, A. K. M. G., Shelest, O., et al. (2021) · Neuron · doi:10.1016/j.neuron.2021.05.020 · Cited by 147 · see citing works
Macroautophagy in CNS health and disease
Griffey, C. J., & Yamamoto, A. (2022) · Nature reviews. Neuroscience · doi:10.1038/s41583-022-00588-3 · Cited by 144 · see citing works
Béland, L.-C., Markovinovic, A., Jakovac, H., De Marchi, F., Bilic, E., Mazzini, L., Kriz, J., & Munitic, I. (2020) · Brain Communications · doi:10.1093/braincomms/fcaa124 · Cited by 125 · see citing works
Gerbino, V., Kaunga, E., Ye, J., Canzio, D., O’Keeffe, S., Rudnick, N. D., Guarnieri, P., Lutz, C. M., & Maniatis, T. (2020) · Neuron · doi:10.1016/j.neuron.2020.03.005 · Cited by 102 · see citing works
ALS- and FTD-associated missense mutations in TBK1 differentially disrupt mitophagy
Harding, O. J., Evans, C. S., Ye, J., Cheung, J., Maniatis, T., & Holzbaur, E. L. F. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2025053118 · Cited by 96 · see citing works
Genetics of Amyotrophic Lateral Sclerosis
Gregory, J. M., Fagegaltier, D., Phatnani, H., & Harms, M. B. (2020) · Current Genetic Medicine Reports · doi:10.1007/s40142-020-00194-8 · Cited by 83 · see citing works
Two FTD-ALS genes converge on the endosomal pathway to induce TDP-43 pathology and degeneration
Shao, W., Todd, T. W., Wu, Y., Jones, C. Y., Tong, J., Jansen‐West, K. R., Daughrity, L. M., Park, J., Koike, Y. M., Kurti, A., et al. (2022) · Science · doi:10.1126/science.abq7860 · Cited by 79 · see citing works
Wu, X., Yang, Z., Zou, J., Gao, H., Shao, Z., Li, C., & Lei, P. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02179-x · Cited by 88 · see citing works
TBK1 (TANK-binding kinase 1)-mediated regulation of autophagy in health and disease
Herhaus, L. (2021) · Matrix Biology · doi:10.1016/j.matbio.2021.01.004 · Cited by 72 · see citing works
Tan, H. Y., Yong, Y. K., Xue, Y. C., Liu, H., Furihata, T., Shankar, E. M., & Ng, C. S. (2022) · iScience · doi:10.1016/j.isci.2022.104404 · Cited by 71 · see citing works
A Systematic Review of Suggested Molecular Strata, Biomarkers and Their Tissue Sources in ALS
Vijayakumar, U. G., Milla, V., Stafford, M. Y. C., Bjourson, A. J., Duddy, W. J., & Duguez, S. (2019) · Frontiers in Neurology · doi:10.3389/fneur.2019.00400 · Cited by 69 · see citing works
The Links between ALS and NF-κB
Källstig, E., McCabe, B. D., & Schneider, B. L. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22083875 · Cited by 59 · see citing works
Implications of Selective Autophagy Dysfunction for ALS Pathology
Vicencio, E., Beltrán, S., Labrador, L., Manque, P., Nassif, M., & Woehlbier, U. (2020) · Cells · doi:10.3390/cells9020381 · Cited by 58 · see citing works
Interplay between immunity and amyotrophic lateral sclerosis: Clinical impact
Marchi, F. D., Munitić, I., Amedei, A., Berry, J. D., Feldman, E. L., Aronica, E., Nardo, G., Weehaeghe, D. V., Niccolai, E., Prtenjača, N., et al. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.06.027 · Cited by 52 · see citing works
Ye, J., Cheung, J., Gerbino, V., Ahlsén, G., Zimanyi, C. M., Hirsh, D., & Maniatis, T. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1915732116 · Cited by 48 · see citing works
The endolysosomal pathway and ALS/FTD
Todd, T. W., Shao, W., Zhang, Y., & Petrucelli, L. (2023) · Trends in Neurosciences · doi:10.1016/j.tins.2023.09.004 · Cited by 44 · see citing works
Overlapping Neuroimmune Mechanisms and Therapeutic Targets in Neurodegenerative Disorders
Marchi, F. D., Munitić, I., Vidatic, L., Papić, E., Rački, V., Nimac, J., Jurak, I., Novotni, G., Rogelj, B., Vuletić, V., et al. (2023) · Biomedicines · doi:10.3390/biomedicines11102793 · Cited by 46 · see citing works
Mitophagy Modulation, a New Player in the Race against ALS
Madruga, E., Maestro, I., & Martı́nez, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22020740 · Cited by 46 · see citing works
TDP-43 Proteinopathy Specific Biomarker Development
Cordts, I., Wachinger, A., Scialò, C., Lingor, P., Polymenidou, M., Buratti, E., & Feneberg, E. (2023) · Cells · doi:10.3390/cells12040597 · Cited by 45 · see citing works
Modelling amyotrophic lateral sclerosis in rodents
Todd, T. W., & Petrucelli, L. (2022) · Nature reviews. Neuroscience · doi:10.1038/s41583-022-00564-x · Cited by 40 · see citing works
Duan, Q., Wang, H., Su, W., Gu, X., Shen, X., Jiang, Z., Ren, Y., Cao, B., Li, G., Wang, Y., et al. (2024) · BMC Medicine · doi:10.1186/s12916-024-03314-1 · Cited by 41 · see citing works
Multiplexed chemogenetics in astrocytes and motoneurons restore blood–spinal cord barrier in ALS
Alami, N. O., Tang, L., Wiesner, D., Commisso, B., Bayer, D., Weishaupt, J. H., Dupuis, L., Wong, P. C., Baumann, B., Wirth, T., et al. (2020) · Life Science Alliance · doi:10.26508/lsa.201900571 · Cited by 39 · see citing works
Self-citationAutophagy-related proteins: Potential diagnostic and prognostic biomarkers of aging-related diseases
Miceli, C., Leri, M., Stefani, M., & Bucciantini, M. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.101967 · Cited by 39 · see citing works
Autophagy Dysfunction in ALS: from Transport to Protein Degradation
Cozzi, M., & Ferrari, V. (2022) · Journal of Molecular Neuroscience · doi:10.1007/s12031-022-02029-3 · Cited by 35 · see citing works
Gut microbiota immune cross-talk in amyotrophic lateral sclerosis
Kaul, M., Mukherjee, D., Weiner, H. L., & Cox, L. M. (2024) · Neurotherapeutics · doi:10.1016/j.neurot.2024.e00469 · Cited by 35 · see citing works
TBK1 interacts with tau and enhances neurodegeneration in tauopathy
Abreha, M. H., Ojelade, S. A., Dammer, E. B., McEachin, Z. T., Duong, D. M., Gearing, M., Bassell, G. J., Lah, J. J., Levey, A. I., Shulman, J. M., et al. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.100760 · Cited by 33 · see citing works
New insights on the disease contribution of neuroinflammation in amyotrophic lateral sclerosis
Chiot, A., Lobsiger, C. S., & Boillée, S. (2019) · Current Opinion in Neurology · doi:10.1097/wco.0000000000000729 · Cited by 28 · see citing works
Self-citationFoster, A., Downing, P., Figredo, E., Polain, N., Stott, A., Layfield, R., & Rea, S. L. (2020) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2020.103539 · Cited by 29 · see citing works
Hemizygous deletion of Tbk1 worsens neuromuscular junction pathology in TDP-43 transgenic mice
Sieverding, K., Ulmer, J., Bruno, C., Satoh, T., Tsao, W., Freischmidt, A., Akira, S., Wong, P. C., Ludolph, A. C., Danzer, K. M., et al. (2020) · Experimental Neurology · doi:10.1016/j.expneurol.2020.113496 · Cited by 28 · see citing works
Self-citationBenson, B. C., Shaw, P. J., Azzouz, M., Highley, J. R., & Hautbergue, G. M. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.783624 · Cited by 28 · see citing works
Targeting common disease pathomechanisms to treat amyotrophic lateral sclerosis
Faller, K. M. E., Chaytow, H., & Gillingwater, T. H. (2025) · Nature Reviews Neurology · doi:10.1038/s41582-024-01049-4 · Cited by 28 · see citing works
Molecular mechanism of PANoptosis and programmed cell death in neurological diseases
Hou, K., Pan, W., Liu, L.-Y., Yu, Q., Ou, J. T., Li, Y., Yang, X., Lin, Z., Yuan, J. H., & Fang, M. (2025) · Neurobiology of Disease · doi:10.1016/j.nbd.2025.106907 · Cited by 29 · see citing works
A TBK1 variant causes autophagolysosomal and motoneuron pathology without neuroinflammation in mice
Brenner, D., Sieverding, K., Srinidhi, J., Zellner, S., Secker, C., Yilmaz, R., Dyckow, J., Amr, S., Ponomarenko, A., Tunaboylu, E., et al. (2024) · The Journal of Experimental Medicine · doi:10.1084/jem.20221190 · Cited by 23 · see citing works
Self-citationRehman, R., Tar, L., Olamide, A. J., Li, Z., Kassubek, J., Böckers, T. M., Weishaupt, J. H., Ludolph, A. C., Wiesner, D., & Roselli, F. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.684171 · Cited by 23 · see citing works
Self-citationProspects for gene replacement therapies in amyotrophic lateral sclerosis
Giovannelli, I., Higginbottom, A., Kirby, J., Azzouz, M., & Shaw, P. J. (2022) · Nature Reviews Neurology · doi:10.1038/s41582-022-00751-5 · Cited by 23 · see citing works
Mitochondria-associated membrane collapse impairs TBK1-mediated proteostatic stress response in ALS
Watanabe, S., Murata, Y., Oka, Y., Oiwa, K., Horiuchi, M., Iguchi, Y., Komine, O., Sobue, A., Katsuno, M., Ogi, T., et al. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2315347120 · Cited by 23 · see citing works
Genetic architecture of motor neuron diseases
Chaudhary, R., Agarwal, V., Rehman, M., Kaushik, A. S., & Mishra, V. (2021) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2021.120099 · Cited by 22 · see citing works
Gurfinkel, Y., Polain, N., Sonar, K., Nice, P. A., Mancera, R. L., & Rea, S. L. (2022) · Neurobiology of Disease · doi:10.1016/j.nbd.2022.105859 · Cited by 19 · see citing works
Plekhg5 controls the unconventional secretion of Sod1 by presynaptic secretory autophagy
Hutchings, A.-J., Hambrecht, B., Veh, A., Giridhar, N. J., Zare, A., Angerer, C., Ohnesorge, T., Schenke, M., Selvaraj, B. T., Chandran, S., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-52875-5 · Cited by 19 · see citing works
Self-citationGlia in amyotrophic lateral sclerosis and spinal cord injury: common therapeutic targets
Ban, J., Sámano, C., Mladinić, M., & Munitić, I. (2019) · Croatian Medical Journal · doi:10.3325/cmj.2019.60.109 · Cited by 17 · see citing works
Immune Signaling Kinases in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD)
García-García, R., Martín-Herrero, L., Blanca-Pariente, L., Pérez-Cabello, J. A., & Roodveldt, C. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222413280 · Cited by 17 · see citing works
Hao, J., Wells, M. F., Niu, G., Juan, I. G. S., Limone, F., Fukuda, A., Leyton-Jaimes, M. F., Joseph, B. J., Qian, M., Mordes, D. A., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.10.11.464011 · Cited by 16 · see citing works
Beckers, J., & Damme, P. V. (2025) · Autophagy Reports · doi:10.1080/27694127.2025.2474796 · Cited by 16 · see citing works
Luan, T., Li, Q., Huang, Z., Feng, Y., Xu, D., Zhou, Y., Hu, Y., & Wang, T. (2024) · Neuroscience Bulletin · doi:10.1007/s12264-024-01267-2 · Cited by 15 · see citing works
Zhan, Y., Huang, J., Tang, X., Du, B., & Yang, B. (2024) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2024.118741 · Cited by 15 · see citing works
Bruno, C., Sieverding, K., Freischmidt, A., Satoh, T., Walther, P., Mayer, B., Ludolph, A. C., Akira, S., Yilmazer‐Hanke, D., Danzer, K. M., et al. (2020) · Brain Communications · doi:10.1093/braincomms/fcaa133 · Cited by 14 · see citing works
Self-citationPeters, O. M., & Brown, R. H. (2022) · Elsevier eBooks · doi:10.1016/b978-0-323-85654-6.00026-5 · Cited by 12 · see citing works
Lenoël, I., Ribon, M., Lorenc, F., Diebold, A., Philibert, C. E., Robaldo, D., Badsi, M., Perronnet, J., Lameth, J., Berriat, F., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-63211-w · Cited by 10 · see citing works
Self-citationDuan, W., Yi, L., Tian, Y., Huang, H.-P., Li, Z., Bi, Y., Guo, M., Li, Y., Liu, Y., Ma, Y., et al. (2021) · Molecular Neurobiology · doi:10.1007/s12035-020-02235-3 · Cited by 10 · see citing works
FUS mutations dominate TBK1 mutations in FUS/TBK1 double-mutant ALS/FTD pedigrees
Brenner, D., Müller, K., Lattante, S., Yilmaz, R., Knehr, A., Freischmidt, A., Ludolph, A. C., Andersen, P. M., & Weishaupt, J. H. (2021) · Neurogenetics · doi:10.1007/s10048-021-00671-4 · Cited by 9 · see citing works
Self-citationCRISPR/Cas9 a genomic engineering technology for treatment in ALS mouse models
Khan, H., Riaz, H., Ahmed, A., Kiyani, M. M., Jawad, S. M., Shah, S. S. U. D., Abualait, T., Al‐Hussain, F., Li, H., & Bashir, S. (2025) · Regenerative Therapy · doi:10.1016/j.reth.2025.07.009 · Cited by 10 · see citing works
Peradinović, J., Mohovic, N., Bulic, K., Markovinović, A., Cimbro, R., & Munitić, I. (2023) · Biology · doi:10.3390/biology12020240 · Cited by 6 · see citing works
Autophagy in motor neuron diseases
Rodríguez‐Muela, N. (2020) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2020.03.009 · Cited by 6 · see citing works
Neuroimmune characterization of optineurin insufficiency mouse model during ageing
Mohovic, N., Peradinović, J., Markovinović, A., Cimbro, R., Minić, Ž., Dominović, M., Jakovac, H., Nimac, J., Rogelj, B., & Munitić, I. (2023) · Scientific Reports · doi:10.1038/s41598-023-38875-3 · Cited by 6 · see citing works
TBK1 is involved in programmed cell death and ALS-related pathways in novel zebrafish models
Raas, Q., Haouy, G., de Calbiac, H., Pasho, E., Marian, A., Guerrera, I. C., Rosello, M., Oeckl, P., Bene, F. D., Catanese, A., et al. (2025) · Cell Death Discovery · doi:10.1038/s41420-025-02374-3 · Cited by 5 · see citing works
Crosstalk and Prospects of TBK1 in Inflammation
Liu, H., Sheng, Q., Dan, J., & Xie, X. (2024) · Immunological Investigations · doi:10.1080/08820139.2024.2392587 · Cited by 4 · see citing works
The role of autophagic kinases in regulation of axonal function
Berth, S. H., Rich, D. J., & Lloyd, T. E. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.996593 · Cited by 4 · see citing works
A chemogenomic approach is required for effective treatment of amyotrophic lateral sclerosis
Pampalakis, G., Angelis, G., Zingkou, E., Vekrellis, K., & Sotiropoulou, G. (2022) · Clinical and Translational Medicine · doi:10.1002/ctm2.657 · Cited by 4 · see citing works
Manganelli, F., Perfetto, C., Carletta, O., & Gerbino, V. (2026) · Cells · doi:10.3390/cells15050477 · Cited by 3 · see citing works
Anjum, F., Hulbah, M. J., Shamsi, A., & Mohammad, T. (2025) · Life · doi:10.3390/life15111665 · Cited by 2 · see citing works
Non-cell autonomous autophagy in amyotrophic lateral sclerosis: A new promising target?
Rosso, F., Magdalena, R., Torazza, C., Bacchetti, F., Milanese, M., Poletti, A., Bonanno, G., Cristofani, R., & Bonifacino, T. (2025) · Neurobiology of Disease · doi:10.1016/j.nbd.2025.107203 · Cited by 3 · see citing works
Innate immune crosstalk in ALS/FTD pathogenesis
Shu, X., Yu, X., Xu, P., & Wang, A. (2026) · Cell Insight · doi:10.1016/j.cellin.2026.100340 · Cited by 2 · see citing works
Khudri, M. M., Hussey, A. J., & Osmani, A. R. (2025) · Applied Economics · doi:10.1080/00036846.2025.2539530 · Cited by 2 · see citing works
TBK1 activity regulates the directionality of axonal transport of signalling endosomes
Villarroel‐Campos, D., Vargas, J. N. S., Chiozzi, R. Z., Brown, A., Wallace, M., Sun, K., Sleigh, J. N., Thalassinos, K., Fratta, P., & Schiavo, G. (2026) · Life Science Alliance · doi:10.26508/lsa.202503527 · Cited by 2 · see citing works
Blowing Hot and Cold in ALS: The Duality of TBK1
Mayl, K., & Sreedharan, J. (2020) · Neuron · doi:10.1016/j.neuron.2020.05.006 · Cited by 2 · see citing works
Veh, A., Ewald, M., Geßner, V. D. C. N., Giridhar, N. J., Hutchings, A.-J., Stigloher, C., Binotti, B., Heinze, K. G., & Lüningschrör, P. (2025) · Translational Neurodegeneration · doi:10.1186/s40035-025-00524-2 · Cited by 1 · see citing works
Self-citationThe Gut Microbiome in Amyotrophic Lateral Sclerosis: Emerging Mechanisms and Therapeutic Potential
Oriquat, G. A., Malathi, H., Maharana, L., Dhyani, A., Al-Hasnaawei, S., Singh‐Chauhan, A., Arora, V., Sharma, J., & Sadeghi-Samarjan, R. (2026) · Molecular Neurobiology · doi:10.1007/s12035-026-05826-8 · Cited by 1 · see citing works
Astrocyte-Neuron Interactions Contributing to Amyotrophic Lateral Sclerosis Progression
Jensen, B. K. (2024) · Advances in neurobiology · doi:10.1007/978-3-031-64839-7_12 · Cited by 1 · see citing works
Rodríguez-Nunez, I., Bartley, S. C., Taylor, J. W., Johnston, S. Q., Rogers, B. B., Meadows, S. K., Newberry, K. M., Cochran, J. N., & Myers, R. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.05.30.657077 · Cited by 1 · see citing works
Regulation of intracellular traffic by TBK1 and its relevance to ALS
Villarroel‐Campos, D. (2020) · UCL Discovery (University College London)
Exercise in the management of motor neuron disease
Lawton, A., & Husaric, M. (2022) · Elsevier eBooks · doi:10.1016/b978-0-323-89843-0.00021-0
TBK1 eliminates aggregation-prone monomeric TDP-43 through the IFNβ-immunoproteasome pathwayPreprint
Sakai, S., Oiwa, K., Iguchi, Y., Watanabe, S., Komine, O., Horiuchi, M., Katsuno, M., & Yamanaka, K. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.04.29.650889
Optineurin Shapes Basal and LPS-Induced Transcriptomes in BV2 Microglia
Cappelli, S., Peradinović, J., Mohovic, N., Mandal, P., Stuani, C., Longo, A., Cannon, J. R., Baloni, P., Leoni, B., Krsmanovic, T., et al. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms262110453
Duan, Q.-Q., Wang, H., Su, W.-M., Gu, X., Shen, X.-F., Jiang, Z., Ren, Y.-L., Cao, B., Li, G.-B., Wang, Y., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26689454
Duan, Q.-Q., Wang, H., Su, W.-M., Gu, X., Shen, X.-F., Jiang, Z., Ren, Y.-L., Cao, B., Li, G.-B., Wang, Y., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26689457
Duan, Q.-Q., Wang, H., Su, W.-M., Gu, X., Shen, X.-F., Jiang, Z., Ren, Y.-L., Cao, B., Li, G.-B., Wang, Y., et al. (2024) · Figshare · doi:10.6084/m9.figshare.25347106
Duan, Q.-Q., Wang, H., Su, W.-M., Gu, X., Shen, X.-F., Jiang, Z., Ren, Y.-L., Cao, B., Li, G.-B., Wang, Y., et al. (2024) · Figshare · doi:10.6084/m9.figshare.25347282
Xinyuan, Y. U., Song, Y. A. O., Xu, P., & Wang, A. (2026) · Journal of Zhejiang University (Medical Sciences) · doi:10.3724/zdxbyxb-2026-0036
Minding the gates: dual cell-autonomous and non-cell-autonomous mechanisms of TBK1 in ALS/FTD
Smeyers, J., & Mordes, D. A. (2026) · Frontiers in Neuroscience · doi:10.3389/fnins.2026.1941293
Sakai, S., Oiwa, K., Iguchi, Y., Akçay, İ. M., Watanabe, S., Komine, O., Nagata, N., Horiuchi, M., Sreedharan, J., Katsuno, M., et al. (2026) · EMBO Reports · doi:10.1038/s44319-026-00953-8
- Authors
- Brenner, D., Sieverding, K., Bruno, C., Lüningschrör, P., Buck, E., Mungwa, S., Fischer, L., Brockmann, S. J., Ulmer, J., Bliederhäuser, C., Philibert, C. E., Satoh, T., Akira, S., Boillée, S., Mayer, B., Sendtner, M., Ludolph, A. C., Danzer, K. M., Lobsiger, C. S., Freischmidt, A., & Weishaupt, J. H.
- Affiliations
- Department of Neurology, University of Ulm, Ulm, Germany 1
- Universität Ulm (DE)
- Universitätsklinikum Würzburg (DE)
- Centre National de la Recherche Scientifique (FR)
- Research Institute for Microbial Diseases, The University of Osaka (JP)
- Corresponding author
- Weishaupt, Jochen H.
- ORCID
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2019-01-11
- Volume
- 216
- Issue
- 2
- Pages
- 267-278
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC6363427
- OpenAlex
- W2909420674
- Cited by
- 83
- References
- 44
- Citations by year
- 2026: 7 · 2025: 14 · 2024: 11 · 2023: 7 · 2022: 11 · 2021: 15 · 2020: 14 · 2019: 4
- FWCI
- 7.44
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Journal of Experimental Medicine (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by-nc-sa)
- Funders
- The Bruno and Ilse Frick Foundation for ALS Research
- Association pour la Recherche sur la Sclérose latérale amyotrophique et autres maladies du motoneurone
- l’Aide à la Recherche des Maladies du Cerveau
- University of Ulm
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Keywords
- TBK1, amyotrophic lateral sclerosis, SOD1 G93A, selective autophagy, motor neuron degeneration, neuroinflammation, microglia, proteostasis, disease progression, second hit
- MeSH terms
- Superoxide Dismutase-1, Loss of Function Mutation, Autophagic Cell Death, Amyotrophic Lateral Sclerosis, Animals, Brain, Disease Models, Animal, Motor Neurons, Superoxide Dismutase, Protein Serine-Threonine Kinases, Gene Deletion, Microglia, Mice, Knockout, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
