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Converging Mechanisms in ALS and FTD: Disrupted RNA and Protein Homeostasis
Open accessAbstract
Breakthrough discoveries identifying common genetic causes for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) have transformed our view of these disorders. They share unexpectedly similar signatures, including dysregulation in common molecular players including TDP-43, FUS/TLS, ubiquilin-2, VCP, and expanded hexanucleotide repeats within the C9ORF72 gene. Dysfunction in RNA processing and protein homeostasis is an emerging theme. We present the case here that these two processes are intimately linked, with disease-initiated perturbation of either leading to further deviation of both protein and RNA homeostasis through a feedforward loop including cell-to-cell prion-like spread that may represent the mechanism for relentless disease progression.
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“Rather, it is a disease of the spinal cord in which astrocytes, microglia, and oligodendrocytes all contribute to disease progression (Ling et al., 2013).”
From An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex (2014) · cites this paper as Ling et al., 2013
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“TDP-43 aggregates have also been associated with approximately 97% of ALS cases [49].”
From Head Injury and Amyotrophic Lateral Sclerosis: Population-Based Study from the National ALS Registry (2025) · cites this paper as [49]
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“The majority of disease-associated FUS mutations affect the C-terminal nuclear localization signal, resulting in cytosolic mislocalization and aggregation of mutant FUS [232–234].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [234]
In the citing paper
“Dysfunction of transactivating response DNA binding protein (TDP43; also known as TARDBP) and fused in sarcoma (FUS; also known as TLS) lead to phenotypes that are characteristic of amyotrophic lateral sclerosis (ALS) and frontal temporal lobar disease (FTLD)”
From The neurogenetics of alternative splicing (2016) · cites this paper as [156]
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“TDP43 is a major component of cytoplasmic inclusions found in 95% cases of sporadic ALS and FTLD156.”
From The neurogenetics of alternative splicing (2016) · cites this paper as [156]
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“Evidence for Gain of RNA Toxicity from C9ORF72 Expansion Intranuclear RNA foci containing the C9ORF72 hexanucleotide repeat have been reported (DeJesus-Hernandez et al., 2011), which may trap one or more RNA-binding proteins, thereby inhibiting their functions, especially in RNA processing (Figure…”
InfluentialA Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD
Renton, A. E., Majounie, E., Waite, A., Simón-Sánchez, J., Rollinson, S., Gibbs, J. R., Schymick, J. C., Laaksovirta, H., van Swieten, J. C., Myllykangas, L., et al. (2011) · Neuron · doi:10.1016/j.neuron.2011.09.010 · Cited by 4,409
Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice
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Mutations in FUS, an RNA Processing Protein, Cause Familial Amyotrophic Lateral Sclerosis Type 6
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Protein S-nitrosylation and oxidation contribute to protein misfolding in neurodegeneration
Nakamura, T., Oh, C.-K., Zhang, X., & Lipton, S. A. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.07.002 · Cited by 84
Ribosome inhibition by C9ORF72-ALS/FTD-associated poly-PR and poly-GR proteins revealed by cryo-EM
Loveland, A. B., Svidritskiy, E., Susorov, D. S., Lee, S., Park, A., Zvornicanin, S. N., Demo, G., Gao, F., & Korostelev, A. A. (2022) · Nature Communications · doi:10.1038/s41467-022-30418-0 · Cited by 86
Emerging Therapies and Novel Targets for TDP-43 Proteinopathy in ALS/FTD
Hayes, L. R., & Kaláb, P. (2022) · Neurotherapeutics · doi:10.1007/s13311-022-01260-5 · Cited by 86
“TDP-43 nuclear clearance and cytoplasmic aggregation in neurons and glia in affected CNS regions of ALS and FTD have been widely observed in sporadic and familial cases, with the notable exceptions of patients with inherited SOD1, FUS, and tau mutations (reviewed in [13]).”
BackgroundMolecular subtypes of ALS are associated with differences in patient prognosis
Eshima, J., O’Connor, S. A., Marschall, E., Bowser, R. P., Plaisier, C. L., & Smith, B. S. (2023) · Nature Communications · doi:10.1038/s41467-022-35494-w · Cited by 81
A U1 snRNP–specific assembly pathway reveals the SMN complex as a versatile hub for RNP exchange
So, B. R., Wan, L., Zhang, Z., Li, P., Babiash, E. S., Duan, J., Younis, I., & Dreyfuss, G. (2016) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.3167 · Cited by 82
“For example, the SMN complex has recently intersected with several major neurodegenerative diseases caused by specific mutations in RBPs, FUS/TLS and TDP-43, which cause amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) 45,56–58 .”
Biology and Pathobiology of TDP-43 and Emergent Therapeutic StrategiesPreprint
Guo, L. E., & Shorter, J. (2016) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a024554 · Cited by 85
“The loss of nuclear TDP-43 in degenerating neurons of ALS patients indicates that a loss of nuclear TDP-43 function likely contributes to disease (Lee et al. 2012; Li et al. 2013; Ling et al. 2013).”
InfluentialSynaptic Paths to Neurodegeneration: The Emerging Role of TDP-43 and FUS in Synaptic Functions
Ling, S. (2018) · Neural Plasticity · doi:10.1155/2018/8413496 · Cited by 85
“The majority of studies in the transgenic animals expressing disease-linked mutations in TDP-43 have been focused on the motor phenotype and ALS-like pathology [2].”
BackgroundInfluentialSelf-citationTDP-43 transports ribosomal protein mRNA to regulate axonal local translation in neuronal axons
Nagano, S., Jinno, J., Abdelhamid, R. F., Jin, Y., Shibata, M., Watanabe, S., Hirokawa, S., Nishizawa, M., Sakimura, K., Onodera, O., et al. (2020) · Acta Neuropathologica · doi:10.1007/s00401-020-02205-y · Cited by 82
In vivo stress granule misprocessing evidenced in a FUS knock-in ALS mouse model
Zhang, X., Wang, F., Hu, Y., Chen, R., Meng, D., Guo, L., Lv, H., Guan, J., & Jia, Y. (2020) · Brain · doi:10.1093/brain/awaa076 · Cited by 83
Song, J. (2021) · Protein Science · doi:10.1002/pro.4079 · Cited by 79
Roy, B., Lee, E. J., Li, T., & Rampersaud, M. (2022) · Genes · doi:10.3390/genes13030425 · Cited by 83
Astrocytic TDP-43 Pathology in Alexander Disease
Walker, A. K., Daniels, C. M. L., Goldman, J. E., Trojanowski, J. Q., Lee, V. M. ‐., & Messing, A. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.0248-14.2014 · Cited by 81
“This is in stark contrast to many previous transgenic mouse models of TDP-43 proteinopathy engineered to overexpress mutant, wild-type, or C-terminal TDP-43 proteins in which little or no TDP-43 pathology is detected in neurons or other cell types (for review, see Ling et al., 2013).”
ResultConti, L. D., Akinyi, M. V., Mendoza-Maldonado, R., Romano, M., Baralle, M., & Buratti, E. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv814 · Cited by 83
“This is consistent with the central role that this protein plays in the control of RNA metabolism and protein homeostasis within cells (7,52) and probably the reason for the tightly regulated expression levels within cells, mostly through an auto regulatory feedback loop mechanism that acts through the 3′UTR of its ow…”
Limanaqi, F., Biagioni, F., Mastroiacovo, F., Polzella, M., Lazzeri, G., & Fornai, F. (2020) · Antioxidants · doi:10.3390/antiox9101022 · Cited by 80
Quadros, A. R. A. D. A., Li, Z., Wang, X., Ndayambaje, I. S., Aryal, S., Ramesh, N., Nolan, M., Jayakumar, R., Han, Y., Stillman, H., et al. (2024) · Acta Neuropathologica · doi:10.1007/s00401-023-02655-0 · Cited by 79
“Notably, TDP-43 pro-teinopathy TDP-43 is an RNA-binding protein encoded by the TARDBP gene that regulates fundamental aspects of RNA metabolism including splicing [20, 48, 49, 53, 71, 74, 90].”
BackgroundSelf-citationBanerjee, A., Vest, K. E., Pavlath, G. K., & Corbett, A. H. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx786 · Cited by 79
Boehringer, A. V., Garcia‐Mansfield, K., Singh, G. M., Bakkar, N., Pirrotte, P., & Bowser, R. P. (2017) · Scientific Reports · doi:10.1038/s41598-017-14924-6 · Cited by 80
Gautam, M., Jara, J. H., Koçak, N., Rylaarsdam, L. E., Kim, K. D., Bigio, E. H., & Özdinler, P. H. (2018) · Acta Neuropathologica · doi:10.1007/s00401-018-1934-8 · Cited by 80
Li, J., Jaiswal, M. K., Chien, J.-F., Kozlenkov, A., Jung, J., Zhou, P., Gardashli, M., Pregent, L., Engelberg-Cook, E., Dickson, D. W., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-41033-y · Cited by 81
“We found multiple differentially acetylated (DA) chromatin regions in C9-ALS subjects compared with controls (FDR < 0.05; Supplementary Dataset 7).”
InfluentialA robust TDP-43 knock-in mouse model of ALS
Huang, S., Wu, L.-S., Lee, M., Chang, C.-W., Cheng, W.-C., Fang, Y.-S., Chen, Y., Cheng, P., & Shen, C.-K. J. (2020) · Acta Neuropathologica Communications · doi:10.1186/s40478-020-0881-5 · Cited by 80
Cryo-EM structure of C9ORF72–SMCR8–WDR41 reveals the role as a GAP for Rab8a and Rab11a
Tang, D., Sheng, J., Xu, L., Zhan, X., Liu, J., Jiang, H., Shu, X., Liu, X., Zhang, T., Jiang, L., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2002110117 · Cited by 82
Sternburg, E. L., da Silva, L. A. G., & Dormann, D. (2021) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2021.07.004 · Cited by 76
Chang, L., & Monteiro, M. J. (2015) · PLoS ONE · doi:10.1371/journal.pone.0130162 · Cited by 80
“Classification of the genes according to their function indicates two large clusters, those involved in protein homeostasis (proteostasis) and RNA metabolism, suggesting that defects in these two systems are a major trigger for ALS [3, 4].”
BackgroundModeling ALS and FTD with iPSC-derived neurons
Lee, S., & Huang, E. J. (2015) · Brain Research · doi:10.1016/j.brainres.2015.10.003 · Cited by 79
“These mutations include missense mutations in genes encoding two RNA/DNA binding proteins, TDP-43 (TARDBP or TAR-DNA-binding protein-43) and FUS/TLS (fused in sarcoma/translocation in liposarcoma or FUS) and the GGGGCC hexanucleotide expansions in C9ORF72 gene (Lee et al., 2012; Ling et al., 2013).”
Ke, Y. D., van Hummel, A., Stevens, C. H., Gladbach, A., Ippati, S., Bi, M., Lee, W. S., Krüger, S., van der Hoven, J., Volkerling, A. M., et al. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1486-0 · Cited by 77
“Neuropathologically, both FTLD and ALS present with pathological deposition of ubiquitinated and aberrantly phosphorylated proteins in neurons and, less frequently, other CNS cell types [29].”
BackgroundTamaki, Y., Shodai, A., Morimura, T., Hikiami, R., Minamiyama, S., Ayaki, T., Tooyama, I., Furukawa, Y., Takahashi, R., & Urushitani, M. (2018) · Scientific Reports · doi:10.1038/s41598-018-24463-3 · Cited by 79
Exploring new pathways of neurodegeneration in ALS: The role of mitochondria quality control
Palomo, G. M., & Manfredi, G. (2014) · Brain Research · doi:10.1016/j.brainres.2014.09.065 · Cited by 81
Peng, A. Y. T., Agrawal, I., Ho, W. Y., Yen, Y.-C., Pinter, A. J., Liu, J., Phua, Q. X. C., Koh, K. B., Chang, J., Sanford, E., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2007806117 · Cited by 77
“As such, loss of normal nuclear TDP-43 function in neurons or glia could contribute to ALS/FTD and other TDP-43 proteinopathy-related diseases (7, 11).”
BackgroundSelf-citationTFEB/Mitf links impaired nuclear import to autophagolysosomal dysfunction in C9-ALS
Cunningham, K. M., Maulding, K., Ruan, K., Şentürk, M., Grima, J. C., Sung, H., Zuo, Z., Song, H., Gao, J., Dubey, S. K., et al. (2020) · eLife · doi:10.7554/elife.59419 · Cited by 80
Yaron, A., & Schuldiner, O. (2016) · Current Biology · doi:10.1016/j.cub.2016.05.025 · Cited by 81
Appocher, C., Mohagheghi, F., Cappelli, S., Stuani, C., Romano, M., Feiguin, F. M., & Buratti, E. (2017) · Nucleic Acids Research · doi:10.1093/nar/gkx477 · Cited by 76
Longitudinal imaging in C9ORF72 mutation carriers: relationship to phenotype
Floeter, M. K., Bageac, D., Danielian, L. E., Braun, L. E., Traynor, B. J., & Kwan, J. Y. (2016) · NeuroImage: Clinical · doi:10.1016/j.nicl.2016.10.014 · Cited by 75
“Different phenotypes could result from distinct disease initiation sites that spread through synaptic connections, or frompatient-specific vulnerabilities of different neurons to themolecular pathways disturbed by the C9orf72mutation (Donnelly et al., 2013; Ling et al., 2013).”
Blood Biomarkers for Amyotrophic Lateral Sclerosis: Myth or Reality?
Robelin, L., & de Aguilar, J. G. (2014) · BioMed Research International · doi:10.1155/2014/525097 · Cited by 83
“Thus, excitotoxicity, oxidative stress, aberrant protein aggregation, defective axonal transport, mitochondrial dysfunction, and altered RNA metabolism have been incriminated in one way or another in the molecular and cellular pathways leading to ALS [7–12].”
BackgroundAltered mRNP granule dynamics in FTLD pathogenesis
Bowden, H. A., & Dormann, D. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13601 · Cited by 75
Exploring the genetics and non-cell autonomous mechanisms underlying ALS/FTLD
Chen, H., Kankel, M. W., Su, S. C., Han, S., & Ofengeim, D. (2018) · Cell Death and Differentiation · doi:10.1038/s41418-018-0060-4 · Cited by 74
Beyond Haemostasis and Thrombosis: Platelets in Depression and Its Co-Morbidities
Izzi, B., Tirozzi, A., Cerletti, C., Donati, M. B., de Gaetano, G., Hoylaerts, M., Iacoviello, L., & Gialluisi, A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21228817 · Cited by 79
“This protein is implicated in the onset of the pathology by contributing to the formation of insoluble intracellular inclusions in neurons, and is present in the majority of ALS cases [305,306].”
BackgroundSproviero, D., Gagliardi, S., Zucca, S., Arigoni, M., Giannini, M., Garofalo, M., Olivero, M., Dell’Orco, M., Pansarasa, O., Bernuzzi, S., et al. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22052737 · Cited by 76
“The aberrant RNA metabolism processing converges as a common factor in the pathogenesis of these diseases [14,15].”
BackgroundTDP-43 pathology: From noxious assembly to therapeutic removal
Keating, S. S., Gil, R. S., Swanson, M. E. V., Scotter, E. L., & Walker, A. K. (2022) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2022.102229 · Cited by 81
Raguseo, F., Wang, Y., Li, J., Petrić, M., Balendra, R., Huyghebaert, A., Vadukul, D. M., Tanase, D. A., Maher, T. E., Malouf, L., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-43872-1 · Cited by 78
“The paper is well written, the idea of the work is good, however in my opinion not all the conclusions are supported by the results.”
ResultPPAR gamma activation is neuroprotective in a Drosophila model of ALS based on TDP-43
Joardar, A., Menzl, J., Podolsky, T. C., Manzo, E., Estes, P. S., Ashford, S., & Zarnescu, D. C. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddu587 · Cited by 76
Ababneh, N. A., Scaber, J., Flynn, R., Douglas, A. G. L., Barbagallo, P., Candalija, A., Turner, M. R., Sims, D., Dafinca, R., Cowley, S. A., et al. (2020) · Human Molecular Genetics · doi:10.1093/hmg/ddaa106 · Cited by 76
Kitamura, A., Nakayama, Y., Shibasaki, A., Taki, A., Yuno, S., Takeda, K., Yahara, M., Tanabe, N., & Kinjo, M. (2016) · Scientific Reports · doi:10.1038/srep19230 · Cited by 77
Do‐Ha, D., Buskila, Y., & Ooi, L. (2017) · Molecular Neurobiology · doi:10.1007/s12035-017-0392-y · Cited by 81
“10% of ALS cases, more than 30 genes have already been implicated [10], with mutations in C9ORF72 and SOD1 accounting for a total of 52% of all fALS cases [11, 12].”
BackgroundLau, D. H. W., Hartopp, N., Welsh, N. J., Mueller, S., Glennon, E. B. C., Mórotz, G. M., Annibali, A., Gómez‐Suaga, P., Stoica, R., Paillusson, S., et al. (2018) · Cell Death and Disease · doi:10.1038/s41419-017-0022-7 · Cited by 77
Baskoylu, S., Yersak, J. M., O’Hern, P., Grosser, S., Simon, J., Kim, S. Y., Schuch, K. N., Dimitriadi, M., Yanagi, K. S., Lins, J., et al. (2018) · PLoS Genetics · doi:10.1371/journal.pgen.1007682 · Cited by 71
The Proline/Arginine Dipeptide from Hexanucleotide Repeat Expanded C9ORF72 Inhibits the Proteasome
Gupta, R., Lan, M., Mojsilovic‐Petrovic, J., Choi, W. H., Safren, N., Barmada, S. J., Lee, M. J., & Kalb, R. G. (2017) · eNeuro · doi:10.1523/eneuro.0249-16.2017 · Cited by 74
Chang, Y.-H., & Dubnau, J. (2019) · Current Biology · doi:10.1016/j.cub.2019.07.071 · Cited by 68
“This likely involves both neuron-to-neuron and glial-to-neuron effects [1, 2, 5].”
Impaired protein degradation in FTLD and related disorders
Götzl, J. K., Lang, C. M., Haass, C., & Capell, A. (2016) · Ageing Research Reviews · doi:10.1016/j.arr.2016.04.008 · Cited by 75
Nakayama, K., Ohashi, R., Shinoda, Y., Yamazaki, M., Abe, M., Fujikawa, A., Shigenobu, S., Futatsugi, A., Noda, M., Mikoshiba, K., et al. (2017) · eLife · doi:10.7554/elife.29677 · Cited by 73
“…memory deficits with low steady-state EPSP and intact LTP, has been reported in other mice such as aged mice, prion-infected mice, chronic stressed mice, and Rett syndrome model (MeCP2-null) mice (Burke and Barnes, 2006; Mallucci et al., 2007; Kallarackal et al., 2013; Dani and Nelson, 2009).”
BackgroundThe ALS-FTD-linked gene product, C9orf72, regulates neuronal morphogenesis via autophagy
Ho, W. Y., Tai, Y. K., Chang, J., Liang, J., Tyan, S.-H., Chen, S., Guan, J., Zhou, H., Shen, H., Koo, E. H., et al. (2019) · Autophagy · doi:10.1080/15548627.2019.1569441 · Cited by 73
Self-citationCell‐to‐cell transmission of C9orf72 poly‐(Gly‐Ala) triggers key features of ALS/FTD
Khosravi, B., LaClair, K. D., Riemenschneider, H., Zhou, Q., Frottin, F., Mareljic, N., Czuppa, M., Farny, D., Hartmann, H., Michaelsen, M., et al. (2020) · The EMBO Journal · doi:10.15252/embj.2019102811 · Cited by 70
“…cytoplasmic aggregates of the nuclear RNA-binding protein TDP-43 are the key feature of sporadic amyotrophic lateral sclerosis (ALS) and define a large subgroup of frontotemporal dementia (FTD) neuropathologically (Geser et al , 2009; Ling et al , 2013; Scotter et al , 2015; Prasad et al , 2019).”
Beijer, D., Kim, H. J., Guo, L. E., O’Donovan, K., Mademan, I., Deconinck, T., Schil, K. V., Fare, C. M., Drake, L. E., Ford, A. F., et al. (2021) · JCI Insight · doi:10.1172/jci.insight.148363 · Cited by 70
“On the one hand, pathological aggregates can cause a toxic gain of function (75).”
BackgroundSundaramoorthy, V., Sultana, J. M., & Atkin, J. D. (2015) · Frontiers in Neuroscience · doi:10.3389/fnins.2015.00400 · Cited by 74
“Interestingly, Golgi fragmentation is often detected as an early event in these conditions, prior to apoptosis (Gosavi et al., 2002; Liazoghli et al., 2005; Atkin et al., 2014; van Dis et al., 2014), suggesting that Golgi fragmentation could be a trigger for neurodegeneration rather than a simple consequence of neuron…”
BackgroundTherapeutic effect of berberine on TDP-43-related pathogenesis in FTLD and ALS
Chang, C.-F., Lee, Y., Lee, K., Lin, H., Chen, C., Shen, C.-K. J., & Huang, C.-C. S. (2016) · Journal of Biomedical Science · doi:10.1186/s12929-016-0290-z · Cited by 74
“In about 95 % of ALS and 50 % of FTD cases, the UBI(+)-inclusions are predominately comprised of TDP-43 [8].”
Traffic jam at the nuclear pore: All roads lead to nucleocytoplasmic transport defects in ALS/FTD
Fallini, C., Khalil, B., Smith, C. L., & Rossoll, W. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104835 · Cited by 71
NUP62 localizes to ALS/FTLD pathological assemblies and contributes to TDP-43 insolubility
Gleixner, A. M., Verdone, B. M., Otte, C. G., Anderson, E. N., Ramesh, N., Shapiro, O. R., Gale, J. R., Mauna, J. C., Mann, J. R., Copley, K. E., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-31098-6 · Cited by 71
Functional overlap and divergence between ALS and bvFTD
Trojsi, F., Esposito, F., Stefano, M. D., Buonanno, D., Conforti, F. L., Corbo, D., Piccirillo, G., Cirillo, M., Monsurrò, M. R., Montella, P., et al. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.06.025 · Cited by 72
“Notably, all these genes may share a common link to cellular RNA dynamics (Ling et al., 2013; Thomas et al., 2012).”
C9orf72 deficiency promotes motor deficits of a C9ALS/FTD mouse model in a dose-dependent manner
Shao, Q., Chen, L., Chang, Q., Zhang, W., Yang, M., & Chen, J. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0685-7 · Cited by 78
Sense and antisense RNA are not toxic in Drosophila models of C9orf72-associated ALS/FTD
Moens, T. G., Mizielinska, S., Niccoli, T., Mitchell, J. S., Thoeng, A., Ridler, C. E., Grönke, S., Eßer, J., Heslegrave, A., Zetterberg, H., et al. (2018) · Acta Neuropathologica · doi:10.1007/s00401-017-1798-3 · Cited by 72
“In recent years, it has become apparent that these diseases represent extremes of a clinical and pathological spectrum of disorders, since genetic evidence shows that either or both of these clinical manifestations can be caused by mutations in the same set of genes [33].”
Aberrant Phase Transitions: Side Effects and Novel Therapeutic Strategies in Human Disease
Verdile, V., Paola, E. D., & Paronetto, M. P. (2019) · Frontiers in Genetics · doi:10.3389/fgene.2019.00173 · Cited by 70
“Since alterations in TDP-43 have been found in 97% of ALS cases and about 50% of FTD cases (Ling et al., 2013), the reduction of ataxin-2 could be used as therapeutic strategy for ALS and FTD treatment (Wils et al.”
BackgroundMutant FUS and ELAVL4 (HuD) Aberrant Crosstalk in Amyotrophic Lateral Sclerosis
De Santis, R., Alfano, V., de Turris, V., Colantoni, A., Santini, L., Garone, M. G., Antonacci, G., Peruzzi, G., Sudria-Lopez, E., Wyler, E., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.05.085 · Cited by 70
“Both the loss of a nuclear function and the gain of a possibly toxic function in the cytoplasm have been proposed as pathological mechanisms contributing to ALS (Ling et al., 2013).”
BackgroundCortical Circuit Dysfunction as a Potential Driver of Amyotrophic Lateral Sclerosis
Brunet, A., Stuart‐Lopez, G., Burg, T., Scekic‐Zahirovic, J., & Rouaux, C. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00363 · Cited by 72
“While the clinical presentations of ALS and FTD are extremely different, about 15% of ALS patients develop over time behavioral and cognitive deficits typical of FTD, and about 15% of FTD patients develop over time motor impairments typical of ALS (Ling et al., 2013).”
BackgroundWu, L.-S., Cheng, W.-C., Chen, C.-Y., Wu, M.-C., Wang, Y., Tseng, Y.-H., Chuang, T., & Shen, C. ‐. J. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0674-x · Cited by 63
Pleiotropic requirements for human TDP-43 in the regulation of cell and organelle homeostasis
Roczniak-Ferguson, A., & Ferguson, S. M. (2019) · Life Science Alliance · doi:10.26508/lsa.201900358 · Cited by 75
“…occur in familial forms of ALS and frontotemporal dementia (FTD) that are caused by mutations in other genes as well as in sporadic forms of these and other neurodegenerative diseases (Amador-Ortiz et al, 2007; Rademakers et al, 2012; Ling et al, 2013; Mackenzie & Neumann, 2016; Ayaki et al, 2018).”
BackgroundHuang, C., Yan, S., & Zhang, Z. (2020) · Translational Neurodegeneration · doi:10.1186/s40035-020-00219-w · Cited by 75
Biomarkers in amyotrophic lateral sclerosis: current status and future prospects
McMackin, R., Bede, P., Ingre, C., Malaspina, A., & Hardiman, O. M. (2023) · Nature Reviews Neurology · doi:10.1038/s41582-023-00891-2 · Cited by 74
“Deposition of TAR DNA-binding protein 43 (TDP43) within the cytoplasm of susceptible neurons is a pathological hallmark in most individuals with ALS and in 45% of individuals with FTD 5 .”
BackgroundInfluentialLi, Y., Liu, Y., Yu, X., Xu, Y., Pan, X., Sun, Y. E., Wang, Y., Song, Y.-H., & Shen, Z. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-02013-w · Cited by 72
“241,242 The mechanisms responsible for this phenomenon remain incompletely understood but may be due to different “ molecular grammars ” involved in their phase separation.”
Ditsworth, D., Maldonado, M., McAlonis‐Downes, M., Sun, S., Seelman, A., Drenner, K., Arnold, E. S., Ling, S., Pizzo, D. P., Ravits, J., et al. (2017) · Acta Neuropathologica · doi:10.1007/s00401-017-1698-6 · Cited by 72
“Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive adult-onset neurodegenerative diseases with overlapping clinical and pathological features [34].”
BackgroundSelf-citationKovanda, A., Leonardis, L., Zidar, J., Koritnik, B., Dolenc‐Grošelj, L., Kovacic, S. R., Curk, T., & Rogelj, B. (2018) · Scientific Reports · doi:10.1038/s41598-018-23139-2 · Cited by 71
Emerging antisense oligonucleotide and viral therapies for amyotrophic lateral sclerosis
Ly, C. V., & Miller, T. M. (2018) · Current Opinion in Neurology · doi:10.1097/wco.0000000000000594 · Cited by 70
FTD and ALS—translating mouse studies into clinical trials
Ittner, L. M., Halliday, G. M., Kril, J. J., Götz, J., Hodges, J. R., & Kiernan, M. C. (2015) · Nature Reviews Neurology · doi:10.1038/nrneurol.2015.65 · Cited by 70
Piol, D., Robberechts, T., & Cruz, S. D. (2023) · Neuron · doi:10.1016/j.neuron.2023.02.028 · Cited by 68
Japtok, J., Lojewski, X., Naumann, M., Klingenstein, M., Reinhardt, P., Sterneckert, J. L., Putz, S., Demestre, M., Boeckers, T. M., Ludolph, A. C., et al. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2015.07.017 · Cited by 68
“Both diseases are linked clinically, pathologically, and mechanistically (Ling et al., 2013; Murphy et al., 2007).”
BackgroundC9orf72 loss-of-function: a trivial, stand-alone or additive mechanism in C9 ALS/FTD?
Braems, E., Swinnen, B., & Bosch, L. V. D. (2020) · Acta Neuropathologica · doi:10.1007/s00401-020-02214-x · Cited by 72
Sun, X., Duan, Y., Qin, C., Li, J., Duan, G., Deng, X., Ni, J., Cao, X., Xiang, K., Tian, K., et al. (2018) · Cell Death and Disease · doi:10.1038/s41419-018-1022-y · Cited by 69
Tseng, Y.-L., Lu, P.-C., Lee, C.-C., He, R., Huang, Y., Tseng, Y., Cheng, T.-J. R., Huang, J. J., & Fang, J. (2023) · Journal of Biomedical Science · doi:10.1186/s12929-023-00921-7 · Cited by 73
“This disparity between degradation efficiency and beneficial results may arise from the loss of function of TDP-43 [85].”
BackgroundesyN: Network Building, Sharing and Publishing
Bean, D. M., Heimbach, J., Ficorella, L., Micklem, G., Oliver, S. G., & Favrin, G. (2014) · PLoS ONE · doi:10.1371/journal.pone.0106035 · Cited by 65
“We used this tool to construct a number of basic Petri net models of pathways using data from Reactome [7] and from the literature [25,30–37].”
MethodRethinking Unconventional Translation in Neurodegeneration
Gao, F., Richter, J. D., & Cleveland, D. W. (2017) · Cell · doi:10.1016/j.cell.2017.10.042 · Cited by 70
“Loss of TDP-43, a key pathological protein in more than 95% of ALS cases (Ling et al., 2013), compromises transcriptioncoupled DNA repair (Hill et al., 2016).”
Self-citationMolecular, functional, and pathological aspects of TDP-43 fragmentation
Chhangani, D., Martín‐Peña, A., & Rincón-Limas, D. E. (2021) · iScience · doi:10.1016/j.isci.2021.102459 · Cited by 65
“These studies suggest that TDP-43 insults could be determined, at least in part, through mechanisms involving production of CTFs, even beyond the ALS-FTD spectrum.”
BackgroundInfluentialScekic‐Zahirovic, J., Sanjuan-Ruiz, I., Kan, V. W. Y., Megat, S., Rossi, P. D., Dieterle, S., Cassel, R., Jamet, M., Kessler, P., Wiesner, D., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-23187-9 · Cited by 64
Self-citationDNA Damage, Defective DNA Repair, and Neurodegeneration in Amyotrophic Lateral Sclerosis
Konopka, A., & Atkin, J. D. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.786420 · Cited by 67
Spinal cord extracts of amyotrophic lateral sclerosis spread TDP-43 pathology in cerebral organoids
Tamaki, Y., Ross, J. P., Alipour, P., Castonguay, C.-E., Li, B., Catoire, H., Rochefort, D. L., Urushitani, M., Takahashi, R., Sonnen, J. A., et al. (2023) · PLoS Genetics · doi:10.1371/journal.pgen.1010606 · Cited by 67
“However, in most sporadic ALS patients pathological pTDP-43 aggregates can be found in the cyto-sol of neurons and glia cells with loss of nuclear TDP-43 [1–3].”
TDP-43-regulated cryptic RNAs accumulate in Alzheimer’s disease brains
Ayuso, V. E., Pickles, S. R., Todd, T. W., Yue, M., Jansen‐West, K. R., Song, Y., Bejarano, J. G., Rawlinson, B. D., Deture, M. A., Graff‐Radford, N. R., et al. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00646-z · Cited by 69
“TDP-43 is a nuclear protein with roles in maintaining RNA homeostasis [17–19].”
BackgroundNuclear trafficking in amyotrophic lateral sclerosis and frontotemporal lobar degeneration
Mihevc, S. P., Darovic, S., Kovanda, A., Česnik, A. B., Župunski, V., & Rogelj, B. (2016) · Brain · doi:10.1093/brain/aww197 · Cited by 62
ALS: Recent Developments from Genetics Studies
Therrien, M., Dion, P. A., & Rouleau, G. A. (2016) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-016-0658-1 · Cited by 65
Wang, T., Xu, W., Qin, M., Yang, Y. A., Bao, P., Shen, F., Zhang, Z., & Xu, J. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.729343 · Cited by 68
“It is a common feature that patients carrying pathogenic mutations at birth will not develop neurodegenerative symptoms until adulthood, even for diseases as severe as ALS (54, 55).”
BackgroundInfluentialMolecular landscape of long noncoding RNAs in brain disorders
Yang, S., Lim, K., Kim, S.-H., & Joo, J. (2020) · Molecular Psychiatry · doi:10.1038/s41380-020-00947-5 · Cited by 66
“C9ORF72 has a critical role in abnormal regulation of RNA metabolism and lysosomal function [145, 146].”
BackgroundDUX4 Role in Normal Physiology and in FSHD Muscular Dystrophy
Mocciaro, E., Runfola, V., Ghezzi, P., Pannese, M., & Gabellini, D. (2021) · Cells · doi:10.3390/cells10123322 · Cited by 65
“Formation of TDP-43 aggregates in FSHD might be either a loss-of-function mechanism contributing to the disease, as reported for ALS [108], or a consequence of the impairment of proteasome function.”
BackgroundInfluentialTDP-43 and other hnRNPs regulate cryptic exon inclusion of a key ALS/FTD risk gene, UNC13A
Koike, Y. M., Pickles, S. R., Ayuso, V. E., Jansen‐West, K. R., Qi, Y. A., Li, Z., Daughrity, L. M., Yue, M., Zhang, Y., Cook, C. N., et al. (2023) · PLoS Biology · doi:10.1371/journal.pbio.3002028 · Cited by 65
Inhibition of nonsense-mediated RNA decay by ER stress
Li, Z., Vuong, J. K., Zhang, M., Stork, C., & Zheng, S. (2016) · RNA · doi:10.1261/rna.058040.116 · Cited by 66
“RNA binding protein TDP-43 is commonly found in the cytoplasmic inclusion bodies of ALS and FTD, and its genetic mutations are linked to familial ALS and FTD (Arai et al. 2006; Neumann et al. 2006; Guo et al. 2011; Polymenidou et al. 2012; Ling et al. 2013).”
BackgroundInfluentialMapping Gene Expression in Excitatory Neurons during Hippocampal Late-Phase Long-Term Potentiation
Chen, P. B., Kawaguchi, R., Blum, C., Achiro, J. M., Coppola, G., O’Dell, T. J., & Martin, K. C. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00039 · Cited by 63
“We isolated both ribosomeassociated RNA and total RNA from each set of mini-slices, and performed TRAP-seq to monitor changes in RNA association with ribosomes specifically in excitatory pyramidal neurons and total RNA sequencing (RNA-seq) to monitor changes in the whole mini-slice transcriptome.”
BackgroundMethodInfluentialmRNP assembly, axonal transport, and local translation in neurodegenerative diseases
Khalil, B., Morderer, D., Price, P. L., Liu, F., & Rossoll, W. (2018) · Brain Research · doi:10.1016/j.brainres.2018.02.018 · Cited by 66
Hayakawa‐Yano, Y., Suyama, S., Nogami, M., Yugami, M., Koya, I., Furukawa, T., Zhou, L., Abe, M., Sakimura, K., Takebayashi, H., et al. (2017) · Genes & Development · doi:10.1101/gad.300822.117 · Cited by 63
“Genetic studies have implicated alternative splicing in a growing list of human diseases (Singh and Cooper 2012; Ling et al. 2013).”
Traumatic injury compromises nucleocytoplasmic transport and leads to TDP-43 pathology
Anderson, E. N., Morera, A. A., Kour, S., Cherry, J. D., Ramesh, N., Gleixner, A., Schwartz, J. C., Ebmeier, C., Old, W., Donnelly, C. J., et al. (2021) · eLife · doi:10.7554/elife.67587 · Cited by 61
“pathology is a hallmark of neurodegeneration and is present in ~97 % of ALS cases, ~45 % of cases with frontotemporal dementia (FTD) (Ling et al., 2013), and ~60 % of AD cases (AmadorOrtiz et al.”
BackgroundInfluentialDysregulated miRNAs as Biomarkers and Therapeutical Targets in Neurodegenerative Diseases
Gentile, G., Morello, G., Cognata, V. L., Guarnaccia, M., Conforti, F. L., & Cavallaro, S. (2022) · Journal of Personalized Medicine · doi:10.3390/jpm12050770 · Cited by 71
Alkhazaali-Ali, Z., Negah, S. S., Boroumand, A. R., & Tavakol‐Afshari, J. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.116899 · Cited by 69
Rapamycin alleviates pathogenesis of a new Drosophila model of ALS-TDP
Cheng, C., Lin, M.-J., & Shen, C.-K. J. (2015) · Journal of Neurogenetics · doi:10.3109/01677063.2015.1077832 · Cited by 66
“Thus, it is desirable to design and generate more transgenic fly models of ALS-TDP or FTLD-TDP with adult stage-specific overexpression of the dTDP or hTDP-43 transgene.”
BackgroundInfluentialUnraveling the Role of RNA Mediated Toxicity of C9orf72 Repeats in C9-FTD/ALS
Kumar, V., Hasan, G. M., & Hassan, M. I. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00711 · Cited by 67
“Further studies reveal the same mutations making the C9orf72 repeat expansion the most common known genetic cause of C9-FTD/ALS to date in an increasing number of patients (Gijselinck et al., 2012; Majounie et al., 2012; Ling et al., 2013).”
BackgroundAutophagy in neuroinflammatory diseases
Muller, S., Brun, S., René, F., Seze, J. D., Loeffler, J., & Jeltsch‐David, H. (2017) · Autoimmunity Reviews · doi:10.1016/j.autrev.2017.05.015 · Cited by 66
Nucleo–cytoplasmic transport defects and protein aggregates in neurodegeneration
Bitetto, G., & Fonzo, A. D. (2020) · Translational Neurodegeneration · doi:10.1186/s40035-020-00205-2 · Cited by 68
“Of note, most patients with ALS carrying the expansions present TDP-43 pathology [95].”
Background
Metadata
- Authors
- Ling, S.-C., Polymenidou, M., & Cleveland, D. W.
- Affiliations
- University of California San Diego (US)
- Corresponding author
- Cleveland, Don W.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2013-08
- Volume
- 79
- Issue
- 3
- Pages
- 416-438
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC4411085
- OpenAlex
- W2073073462
- Cited by
- 1,811
- References
- 260
- Citations by year
- 2026: 124 · 2025: 156 · 2024: 149 · 2023: 166 · 2022: 137 · 2021: 170 · 2020: 175 · 2019: 129 · 2018: 139 · 2017: 130 · 2016: 126 · 2015: 98 · 2014: 99 · 2013: 12
- FWCI
- 14.56
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 371 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Ludwig Institute for Cancer Research
- National Institutes of Health (K99-NS075216, R01-NS27036)
- National Institute on Aging (T32 AG 000216)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Keywords
- amyotrophic lateral sclerosis, frontotemporal dementia, RNA homeostasis, proteostasis, TDP-43, FUS/TLS, UBQLN2, VCP, C9orf72 repeat expansion, RNA processing, prion-like spread, feed-forward loop, disease progression
- MeSH terms
- Autophagy-Related Proteins, C9orf72 Protein, Valosin Containing Protein, Adenosine Triphosphatases, Amyotrophic Lateral Sclerosis, Animals, DNA-Binding Proteins, Homeostasis, Humans, Models, Biological, Mutation, Proteins, RNA, Ubiquitins, Cell Cycle Proteins, RNA-Binding Protein FUS, Adaptor Proteins, Signal Transducing, Frontotemporal Dementia
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