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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
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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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]
Experimental — accuracy not yet measuredIn the citing paper
“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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Rosen, D. R., Siddique, T., Patterson, D., Figlewicz, D. A., Sapp, P., Hentati, A., Donaldson, D., Goto, J., O'Regan, J. P., Deng, H.-X., et al. (1993) · Nature · doi:10.1038/362059a0 · Cited by 7,062
Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis
Neumann, M., Sampathu, D. M., Kwong, L. K., Truax, A. C., Micsenyi, M. C., Chou, T. T., Bruce, J., Schuck, T., Grossman, M., Clark, C. M., et al. (2006) · Science · doi:10.1126/science.1134108 · Cited by 6,576
DeJesus-Hernandez, M., Mackenzie, I. R., Boeve, B. F., Boxer, A. L., Baker, M., Rutherford, N. J., Nicholson, A. M., Finch, N. A., Flynn, H., Adamson, J., et al. (2011) · Neuron · doi:10.1016/j.neuron.2011.09.011 · Cited by 4,936 · cited 5×
“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
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
Loss of autophagy in the central nervous system causes neurodegeneration in mice
Komatsu, M., Waguri, S., Chiba, T., Murata, S., Iwata, J.-I., Tanida, I., Ueno, T., Koike, M., Uchiyama, Y., Kominami, E., et al. (2006) · Nature · doi:10.1038/nature04723 · Cited by 3,500
Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17
Hutton, M., Lendon, C. L., Rizzu, P., Baker, M., Froelich, S., Houlden, H., Pickering-Brown, S., Chakraverty, S., Isaacs, A., Grover, A., et al. (1998) · Nature · doi:10.1038/31508 · Cited by 3,498
Arai, T., Hasegawa, M., Akiyama, H., Ikeda, K., Nonaka, T., Mori, H., Mann, D., Tsuchiya, K., Yoshida, M., Hashizume, Y., et al. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2006.10.093 · Cited by 2,732
TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis
Sreedharan, J., Blair, I. P., Tripathi, V. B., Hu, X., Vance, C., Rogelj, B., Ackerley, S., Durnall, J. C., Williams, K. L., Buratti, E., et al. (2008) · Science · doi:10.1126/science.1154584 · Cited by 2,630
Mutations in FUS, an RNA Processing Protein, Cause Familial Amyotrophic Lateral Sclerosis Type 6
Vance, C. A., Rogelj, B., Hortobágyi, T., Vos, K. J. D., Nishimura, A. L., Sreedharan, J., Hu, X., Smith, B. N., Ruddy, D., Wright, P. D., et al. (2009) · Science · doi:10.1126/science.1165942 · Cited by 2,625
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C9ORF72 expression and cellular localization over mouse development
Atkinson, R. A. K., Fernández-Martos, C. M., Atkin, J. D., Vickers, J. C., & King, A. E. (2015) · Acta Neuropathologica Communications · doi:10.1186/s40478-015-0238-7 · Cited by 45
FUS-regulated RNA metabolism and DNA damage repair
Zhou, Y., Liu, S., Öztürk, A., & Hicks, G. G. (2014) · Rare Diseases · doi:10.4161/rdis.29515 · Cited by 50
“Most FUS mutations are dominant missense point mutations, with very few insertion, deletion or truncations observed.(6) The mutations are clustered in two major regions, the extreme C-terminus containing a nuclear localization signal (NLS) and the first glycine-rich region located between the amino-transcriptional dom…”
InfluentialSynaptic FUS Localization During Motoneuron Development and Its Accumulation in Human ALS Synapses
Deshpande, D., Higelin, J., Schoen, M., Vomhof, T., Boeckers, T. M., Demestre, M., & Michaelis, J. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00256 · Cited by 40
Jiang, J., & Ravits, J. (2019) · Neurotherapeutics · doi:10.1007/s13311-019-00797-2 · Cited by 44
“Genetically, mutations in several genes cause either ALS or FTD [4].”
BackgroundBhopatkar, A. A., Uversky, V. N., & Rangachari, V. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.011501 · Cited by 40
“Because TDP-43–based neuropathology is present in 50% of FTLD and 97% of ALS cases (17), the protein represents a molecular link connecting these neurodegenerative diseases as a clinicopathological spectrum of the proteinopathies (15, 18–20).”
BackgroundMolecular structure of an amyloid fibril formed by FUS low-complexity domain
Sun, Y., Zhang, S., Hu, J., Tao, Y., Xia, W., Gu, J., Li, Y., Cao, Q., Li, D., & Liu, C. (2021) · iScience · doi:10.1016/j.isci.2021.103701 · Cited by 39
“1 ll OPEN ACCESS 2008; Ju et al., 2011; Lagier-Tourenne et al., 2012; Ling et al., 2013; Fujii et al., 2005).”
Luan, W., Wright, A. L., Brown-Wright, H., Le, S., Gil, R. S., Martin, L. M. S., Ling, K., Jafar‐Nejad, P., Rigo, F., & Walker, A. K. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-02036-9 · Cited by 41
“Intercross breeder and experimental mice were fed with chow containing 200mg/kg doxycycline (Dox) (Specialty Feeds, Australia).”
MethodDisrupting pathologic phase transitions in neurodegeneration
Hurtle, B. T., Xie, L., & Donnelly, C. J. (2023) · Journal of Clinical Investigation · doi:10.1172/jci168549 · Cited by 40
Kodavati, M. M., Wang, H., Guo, W., Mitra, J., Hegde, P. M., Provasek, V. E., Rao, V. H. M., Vedula, I., Zhang, A., MITRA, S. P., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-45978-6 · Cited by 41
Jiang, T., Ruan, N., Luo, P., Wang, Q., Wei, X., Li, Y., Dai, Y., Li, L., Lv, J., Liu, Y., et al. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102320 · Cited by 43
“Following AD, FTD is identified as the second leading cause of dementia (Ling et al., 2013).”
BackgroundStress granule formation helps to mitigate neurodegeneration
Glineburg, M. R., Yildirim, E., Gómez, N., Rodriguez, G., Pak, J., Li, X., Altheim, C. H., Waksmacki, J., McInerney, G. M., Barmada, S. J., et al. (2024) · Nucleic Acids Research · doi:10.1093/nar/gkae655 · Cited by 39
Biofluid biomarkers in Alzheimer’s disease and other neurodegenerative dementias
Zetterberg, H., & Bendlin, B. B. (2026) · Nature · doi:10.1038/s41586-025-10018-w · Cited by 45
“Pathological mislocalization and aggregation of TDP-43 are hallmarks of several neurodegenerative disorders, including ALS and FTD, implicating a central role in disease pathogenesis.”
InfluentialRudich, P. D., Snoznik, C., Watkins, S. C., Monaghan, J., Pandey, U. B., & Lamitina, S. T. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx372 · Cited by 41
Walker, C., & El‐Khamisy, S. F. (2018) · Brain · doi:10.1093/brain/awy076 · Cited by 40
“This would be of significance as 97% of ALS cases display TDP-43 proteinopathy (Neumann et al., 2006; Ling et al., 2013).”
BackgroundNeuronal RNP granules: from physiological to pathological assemblies
Graeve, F. D., & Besse, F. (2018) · Biological Chemistry · doi:10.1515/hsz-2018-0141 · Cited by 43
Using induced pluripotent stem cell neuronal models to study neurodegenerative diseases
Zhang, X., Hu, D., Shang, Y., & Qi, X. (2019) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2019.03.004 · Cited by 36
“Expansions of a hexanucleotide repeat (GGGGCC) in the noncoding region of the C9ORF72 gene are the most common cause of the familial form of ALS (C9-ALS), as well as frontotemporal lobar degeneration and other neurological diseases [122, 123].”
BackgroundGautam, M., Xie, E. F., Koçak, N., & Özdi̇nler, P. H. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00489 · Cited by 37
“TDP-43 regulates various aspect of RNA metabolism including RNA processing, miRNA biogenesis, and RNA splicing (Ling et al., 2013).”
BackgroundMurray, D. T., & Tycko, R. (2020) · Biochemistry · doi:10.1021/acs.biochem.9b00892 · Cited by 39
Progranulin in neurodegenerative dementia
Wang, X., Zeng, P. H., Fang, Y., Zhang, T., & Tian, Q. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15378 · Cited by 39
“…of genes and is a major component of neuronal and glial aggregates in the brains of tau- negative FTLD, AD, DLB, HS, ALS- D, and TBI patients with dementia (Amador- Ortiz et al., 2007; Arai et al., 2006; Flanagan et al., 2018; Heyburn et al., 2019; Ling et al., 2013; Neumann et al., 2006).”
BackgroundGuo, L., Mao, Q., He, J., Liu, X., Piao, X., Luo, L., Hao, X., Yu, H., Song, Q., Xiao, B., et al. (2023) · Cell Research · doi:10.1038/s41422-023-00798-z · Cited by 34
SUN1 facilitates CHMP7 nuclear influx and injury cascades in sporadic amyotrophic lateral sclerosis
Baskerville, V., Rapuri, S., Mehlhop, E., & Coyne, A. N. (2023) · Brain · doi:10.1093/brain/awad291 · Cited by 41
Neuroprotective agents target molecular mechanisms of disease in ALS
Zhu, Y., Fotinos, A., Mao, L. L. J., Atassi, N., Zhou, E., Ahmad, S., Guan, Y., Berry, J. D., Cudkowicz, M., & Wang, X. (2014) · Drug Discovery Today · doi:10.1016/j.drudis.2014.08.016 · Cited by 39
László, Z. I., Hindley, N., Avila, A. S., Kline, R., Eaton, S. L., Lamont, D. J., Smith, C., Spires‐Jones, T. L., Wishart, T. M., & Henstridge, C. M. (2022) · Acta Neuropathologica Communications · doi:10.1186/s40478-022-01455-z · Cited by 39
TDP-43 seeding induces cytoplasmic aggregation heterogeneity and nuclear loss of function of TDP-43
Rummens, J., Khalil, B., Yıldırım, G., Silva, P., Zorzini, V., Peredo, N., Wojno, M., Ramakers, M., Bosch, L. V. D., Damme, P. V., et al. (2025) · Neuron · doi:10.1016/j.neuron.2025.03.004 · Cited by 39
“…TDP-43 accumulate in neurons and glia of (cid:1) 97% of amyotrophic lateral sclerosis (ALS) and (cid:1) 45% of frontotemporal dementia (FTD) cases, 3 as well as a number of other neurodegenerative diseases such as Alzheimer’s disease (AD) and limbic-predominant age-related TDP-43 encephalopathy…”
Molecular mechanisms and consequences of TDP-43 phosphorylation in neurodegeneration
Kellett, E. A., Bademosi, A. T., & Walker, A. K. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00839-8 · Cited by 47
“Among these proteins, TAR DNA-binding protein 43 (TDP-43) is the primary aggregating protein driving pathology in approximately 97% of ALS, 50% of FTD, and all LATE cases [1, 2].”
TDP-43 nuclear loss in FTD/ALS causes widespread alternative polyadenylation changes
Zeng, Y., Lovchykova, A., Akiyama, T., Rayner, S. L., Jawahar, V. M., Liu, C., Sianto, O., Guo, C., Calliari, A., Prudencio, M., et al. (2025) · Nature Neuroscience · doi:10.1038/s41593-025-02049-3 · Cited by 74
“Defects in RNA metabolism are considered central to frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) pathogenesis 3 .”
Lim, M. A., Bence, K. K., Sandesara, I., Andreux, P. A., Auwerx, J. H., Ishibashi, J., Seale, P., & Kalb, R. G. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddu214 · Cited by 37
Gene panels and primers for next generation sequencing studies on neurodegenerative disorders
Giau, V. V., An, S. S. A., Bagyinszky, E., & Kim, S. (2015) · Molecular & Cellular Toxicology · doi:10.1007/s13273-015-0011-9 · Cited by 37
Posa, D., Martínez‐González, L., Bartolomé, F. B., Nagaraj, S., Porras, G., Martı́nez, A., & Martín‐Requero, Á. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-1249-8 · Cited by 37
Upregulation of ATG7 attenuates motor neuron dysfunction associated with depletion of TARDBP/TDP-43
Donde, A., Sun, M., Jeong, Y. H., Wen, X., Ling, J. P., Lin, S. Z., Braunstein, K. E., Nie, S., Wang, S., Chen, L., et al. (2019) · Autophagy · doi:10.1080/15548627.2019.1635379 · Cited by 39
“In ALS-FTD, TARDBP is depleted from the nuclei, but accumulates in ubiquitinated inclusions of affected neurons andglia, suggesting that loss of normalTARDBP function or, alternatively, gain of a toxic property by cytoplasmic TARDBP aggregates, play roles in the pathogenesis of these illnesses [8].”
BackgroundYamoah, A., Tripathi, P., Sechi, A. S., Köhler, C. N., Guo, H., Chandrasekar, A., Nolte, K. W., Wruck, C. J., Katona, I., Anink, J. J., et al. (2020) · Journal of Alzheimer s Disease · doi:10.3233/jad-190722 · Cited by 35
“Similarly,recentstudieshaveemphasizedafunc-tional interplay between ER function, autophagy, and RNA binding protein (RBP) homeostasis [27].”
Golgi Apparatus: A Potential Therapeutic Target for Autophagy-Associated Neurological Diseases
Deng, S., Liu, J., Wu, X., & Lu, W. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.564975 · Cited by 37
Stress Granule Assembly Can Facilitate but Is Not Required for TDP-43 Cytoplasmic Aggregation
Fernandes, N., Nero, L., Lyons, S. M., Ivanov, P. V., Mittelmeier, T. M., Bolger, T. A., & Buchan, J. R. (2020) · Biomolecules · doi:10.3390/biom10101367 · Cited by 43
“Approximately 90% and 10% of cases are sporadic and familial, respectively [1].”
BackgroundMind the Gap: Mitochondria and the Endoplasmic Reticulum in Neurodegenerative Diseases
Leal, N. S., & Martins, L. M. (2021) · Biomedicines · doi:10.3390/biomedicines9020227 · Cited by 40
O-GlcNAcylation of TDP-43 suppresses proteinopathies and promotes TDP-43’s mRNA splicing activity
Zhao, M., Xiao, Y., Wei, P. Y., Zhao, C. N., Cheng, M., Zhang, D., Xue, W., He, W.-T., Xue, W., Zuo, X., et al. (2021) · EMBO Reports · doi:10.15252/embr.202051649 · Cited by 38
“TDP-43 pathology is a disease hallmark identified in most amyotrophic lateral sclerosis (ALS) and ~ 50% of frontotemporal lobar degeneration (FTLD) patients (Arai et al, 2006; Neumann et al, 2006; Ling et al, 2013).”
Baskoylu, S., Chapkis, N., Unsal, B., Lins, J., Schuch, K. N., Simon, J., & Hart, A. C. (2022) · Cell Reports · doi:10.1016/j.celrep.2021.110195 · Cited by 39
The role of cell adhesion molecules in brain wiring and neuropsychiatric disorders
Sakurai, T. (2016) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2016.08.005 · Cited by 42
“…is neurodegenerative disorders, such as Alzheimer’s disease and ALS: Responsible genes/molecules have been identified, but we still do not have complete pictures of AC C EP TE D M AN U SC R IP T the pathogenesis and pathophysiology of these disorders (Ling et al. 2013, Selkoe and Hardy 2016).”
Loss of TDP-43 induces synaptic dysfunction that is rescued by UNC13A splice-switching ASOsPreprint
Keuss, M. J., Harley, P., Ryadnov, E. M., Jackson, R. E., Zanovello, M., Wilkins, O. G., Barattucci, S., Mehta, P. R., Oliveira, M. G., Parkes, J. E., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.06.20.599684 · Cited by 46
Molecular Investigations of Protein Aggregation in the Pathogenesis of Amyotrophic Lateral Sclerosis
Duranti, E., & Villa, C. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms24010704 · Cited by 40
“aggregation are observed in approximately 97% of all ALS cases, including all sALS cases, whereas SOD1 (2%) and FUS (1%) inclusions are associated with the remaining cases [36].”
BackgroundZhang, H., Gu, J., Zhang, Y., Guo, H., Zhang, S., Song, J., Liu, C., Wang, L. F., Li, D., & Dai, B. (2023) · ACS Nano · doi:10.1021/acsnano.3c00001 · Cited by 36
Benatar, M. G., Hansen, T., Rom, D., Geist, M. A., Blaettler, T., Camu, W., Kuźma‐Kozakiewicz, M., van den Berg, L. H., Morales, R. J., Chiò, A., et al. (2024) · The Lancet Neurology · doi:10.1016/s1474-4422(24)00134-0 · Cited by 39
Umapathy, S., Pan, I., Issac, P. K., Kumar, M. S. K., Giri, J. P., Guru, A., & Arockiaraj, J. (2024) · Molecular Neurobiology · doi:10.1007/s12035-024-04253-x · Cited by 37
“Mutations in the microtubule-associated protein tau, PGRN, and SOD1 gene alter the microtubule-associated protein tau, progranulin, and the antioxidant enzyme copper/zinc SOD1 [120].”
SUMO3 Modification Accelerates the Aggregation of ALS-Linked SOD1 Mutants
Niikura, T., Kita, Y. A., & Abe, Y. (2014) · PLoS ONE · doi:10.1371/journal.pone.0101080 · Cited by 38
“like aggregation and has spreading ability [26].”
Donlin-Asp, P., Rossoll, W., & Bassell, G. J. (2017) · FEBS Letters · doi:10.1002/1873-3468.12621 · Cited by 38
“It shows a significant overlap in genetics, histopathology, and clinical features with frontotemporal dementia (FTD), the most common form of presenile dementia, suggesting that both diseases are part of a disease spectrum [109].”
BackgroundJantrapirom, S., Piccolo, L. L., Yoshida, H., & Yamaguchi, M. (2017) · Experimental Cell Research · doi:10.1016/j.yexcr.2017.12.010 · Cited by 36
Endo, R., Takashima, N., Nekooki-Machida, Y., Komi, Y., Hui, K. K., Takao, M., Akatsu, H., Murayama, S., Sawa, A., & Tanaka, M. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2018.03.008 · Cited by 35
“In FTLD patient brain, TAR DNA-binding protein 43 (TDP-43) is a major component of ubiquitin-positive hyper-phosphorylated inclusions (5), suggesting that its aggregation is implicated in FTLD pathogenesis (6,7).”
Suzuki, H., Shibagaki, Y., Hattori, S., & Matsuoka, M. (2018) · Cell Death and Disease · doi:10.1038/s41419-018-1028-5 · Cited by 38
Exploring the aggregation-prone regions from structural domains of human TDP-43
Kumar, V., Wahiduzzaman, Prakash, A., Tomar, A. K., Srivastava, A., Kundu, B., Lynn, A. M., & Hassan, M. I. (2018) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2018.10.008 · Cited by 37
Kankel, M. W., Sen, A., Lü, L., Theodorou, M., Dimlich, D. N., McCampbell, A., Henderson, C. E., Shneider, N. A., & Artavanis‐Tsakonas, S. (2020) · Genetics · doi:10.1534/genetics.119.302985 · Cited by 35
Neuronal RNA‐binding protein dysfunction in multiple sclerosis cortex
Salapa, H. E., Hutchinson, C., Popescu, B. F. G., & Levin, M. C. (2020) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.51103 · Cited by 36
“In ALS, there is a correlation with the degree of mislocalization and disease severity in that increased amounts of cytoplasmic RBPs are associated with more severe forms of disease.(25,26) Several hypotheses have been proposed to explain the pathological and damaging effects of RBP mislocalization.”
BackgroundJagaraj, C. J., Parakh, S., & Atkin, J. D. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.581950 · Cited by 38
“…in the Chromosome 9 open reading frame 72 (C9orf72) gene (DejesusHernandez et al., 2011; Renton et al., 2011; Bigio, 2012; Lee Y.-B. et al., 2013; Ling et al., 2013; Balendra and Isaacs, 2018), followed by mutations in superoxide dismutase 1 (SOD1; 20%), TARDBP (4–5%), encoding TAR DNA-Binding…”
BackgroundHuangfu, N., Wang, Y., Xu, Z., Zheng, W., Tao, C., Li, Z., Hu, Y., & Chen, X. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.687169 · Cited by 37
Laferrière, F., & Polymenidou, M. (2015) · Swiss Medical Weekly · doi:10.4414/smw.2015.14054 · Cited by 43
Self-citationYu, Y., Nakagawa, T., Morohoshi, A., Nakagawa, M., Ishida, N., Suzuki, N., Aoki, M., & Nakayama, K. (2019) · Human Molecular Genetics · doi:10.1093/hmg/ddz119 · Cited by 38
Disease-modifying effects of metabolic perturbations in ALS/FTLD
Jawaid, A., Khan, R., Polymenidou, M., & Schulz, P. E. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0294-0 · Cited by 37
Self-citationMa, Q., Xin, J., Peng, Q., Li, N., Sun, S., Hou, H., Ma, G., Wang, N., Zhang, L., Tam, K. Y., et al. (2023) · EMBO Reports · doi:10.15252/embr.202255859 · Cited by 35
“Intriguingly, UBQLN2 contains a unique proline-rich region (PXX) which differs from other UBQLN family proteins and displays a high risk for ALS/FTD-linked mutations (Deng et al , 2011; Ling et al , 2013; Fahed et al , 2014).”
InfluentialNonsense-mediated mRNA decay in neuronal physiology and neurodegeneration
Petrić, M., & Patani, R. (2023) · Trends in Neurosciences · doi:10.1016/j.tins.2023.07.001 · Cited by 35
“Notably, TDP-43 proteinopathy is also a pathological hallmark of ~45% of all FTD cases [41].”
BackgroundCurrent insights in the molecular genetic pathogenesis of amyotrophic lateral sclerosis
Zhou, W., & Xu, R. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1189470 · Cited by 39
Al-Khayri, J. M., Ravindran, M., Banadka, A., Devaiah, V. C., Priya, K., Nagella, P., & Kukkemane, K. (2024) · Pharmaceuticals · doi:10.3390/ph17101391 · Cited by 42
Ediriweera, G. R., Sivaram, A. J., Cowin, G., Brown, M. L., McAlary, L., Lum, J. S., Fletcher, N. L., Robinson, L., Simpson, J. D., Chen, L., et al. (2024) · Journal of Controlled Release · doi:10.1016/j.jconrel.2024.11.074 · Cited by 41
Mashiko, T., Sakashita, E., Kasashima, K., Tominaga, K., Kuroiwa, K., Nozaki, Y., Matsuura, T., Hamamoto, T., & Endo, H. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.712232 · Cited by 35
“TDP-43 contains two RNA recognition motifs (RRMs) and plays important roles in RNA metabolism such as RNA processing, exporting, and stabilizing and translational regulation between the nucleus and cytoplasm (10).”
BackgroundLi, S., Chen, Y., Sun, D., Bai, R., Gao, X., Yang, Y., Sheng, J., & Xu, Z. (2017) · Molecular Neurobiology · doi:10.1007/s12035-017-0396-7 · Cited by 35
“In particular, a missense mutation in exon 1 (g.4068C>A) introduces a charged amino acid in the hydrophobic core of the signal peptide at residue 9 (p.A9D) and affects individuals in a large FTLD-U kindred of European ancestry (HDDD2), as well as three independently identified individuals with FTD/FTLD-U [21, 22].”
ResultPrakash, A., Kumar, V., Meena, N. K., Hassan, M. I., & Lynn, A. M. (2017) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2017.1422026 · Cited by 34
“TDP-43-positive inclusions have also been found in other neurodegenerative diseases like Alzheimer disease (AD), Parkinson diseases (PD), dementia with Lewy bodies (DLB), Pick’s disease, and corticobasal degeneration (Hasegawa et al., 2011; Josephs et al., 2014; Ling et al., 2013).”
BackgroundCharacterization of the lncRNA transcriptome in mESC-derived motor neurons: Implications for FUS-ALS
Biscarini, S., Capauto, D., Peruzzi, G., Lü, L., Colantoni, A., Santini, T., Shneider, N. A., Caffarelli, E., Laneve, P., & Bozzoni, I. (2018) · Stem Cell Research · doi:10.1016/j.scr.2018.01.037 · Cited by 35
Non-genetically modified models exhibit TARDBP mRNA increase due to perturbed TDP-43 autoregulation
Sugai, A., Kato, T., Koyama, A., Koike, Y. M., Konno, T., Ishihara, T., & Onodera, O. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.104534 · Cited by 34
Jury, N., Abarzúa, S., Díaz, I. D. P., Guerra, M. V., Ampuero, E., Cubillos, P., Martínez, P., Herrera-Soto, A., Arredondo, C., Rojas, F., et al. (2020) · Clinical Epigenetics · doi:10.1186/s13148-020-0816-9 · Cited by 35
“, haploinsufficiency) and gain-of-toxicity from repeat-containing RNAs and aberrant dipeptide-repeat (DPR) proteins, through repeat-associated non-AUG-dependent (RAN) translation [4, 5, 9, 10].”
Genç, B., Gautam, M., Gözütok, Ö., Dervishi, I., Sanchez, S. S., Goshu, G. M., Koçak, N., Xie, E. F., Silverman, R. B., & Özdi̇nler, P. H. (2021) · Clinical and Translational Medicine · doi:10.1002/ctm2.336 · Cited by 33
Wright, A. L., Gatta, P. A. D., Le, S., Berning, B. A., Mehta, P. M., Jacobs, K. R., Gul, H., Gil, R. S., Hedl, T. J., Riddell, W. R., et al. (2021) · European Journal of Neuroscience · doi:10.1111/ejn.15422 · Cited by 30
Lipid Metabolic Alterations in the ALS–FTD Spectrum of Disorders
Godoy-Corchuelo, J. M., Fernández-Beltrán, L. C., Ali, Z., Gil-Moreno, M. J., López-Carbonero, J. I., Guerrero-Sola, A., Larrad-Sainz, A., Matias-Guiu, J., Matias-Guiu, J. A., Cunningham, T. J., et al. (2022) · Biomedicines · doi:10.3390/biomedicines10051105 · Cited by 35
Block, N., Sha, S. J., Karydas, A. M., Fong, J. C., May, M. G. D., Miller, B. L., & Rosen, H. J. (2015) · American Journal of Geriatric Psychiatry · doi:10.1016/j.jagp.2015.04.007 · Cited by 35
Swain, A., Misulovin, Z., Pherson, M., Gause, M., Mihindukulasuriya, K. A., Rickels, R. A., Shilatifard, A., & Dorsett, D. (2016) · PLoS Genetics · doi:10.1371/journal.pgen.1006331 · Cited by 33
“The TDP-43 ortholog of TBPH is involved in multiple types of RNA processing [37, 38].”
BackgroundATP and nucleic acids competitively modulate LLPS of the SARS-CoV2 nucleocapsid protein
Dang, M., Li, T., & Song, J. (2023) · Communications Biology · doi:10.1038/s42003-023-04480-3 · Cited by 34
The pathogenic mechanism of TAR DNA-binding protein 43 (TDP-43) in amyotrophic lateral sclerosis
Wang, X., Hu, Y., & Xu, R. (2023) · Neural Regeneration Research · doi:10.4103/1673-5374.382233 · Cited by 37
“It has been revealed that TDP-43 can accumulate in the mitochondria of neurons from ALS/FTLD patients, and the suppressing TDP-43 mitochondrial localization eliminates the mitochondrial dysfunction and the neuron loss caused by both WT and mutant TDP-43, even improved the phenotype of transgenic TDP-43 mouse (Wang et…”
BackgroundInfluentialSeeded aggregation of TDP-43 induces its loss of function and reveals early pathological signatures
Scialò, C., Zhong, W., Jagannath, S., Wilkins, O. G., Caredio, D., Hruška-Plocháň, M., Lurati, F., Peter, M., Cecco, E. D., Celauro, L., et al. (2025) · Neuron · doi:10.1016/j.neuron.2025.03.008 · Cited by 43
“27,28 Although the co-occurrence of TDP-43 cytoplasmic accumulation and nuclear clearance has been recognized since the earliest neuropathological descriptions, 1 a mechanistic connection between these two phenomena has not been fully elucidated.”
Self-citationWong, C., & Venkatachalam, K. (2019) · Human Molecular Genetics · doi:10.1093/hmg/ddz104 · Cited by 34
Cytosolic calcium regulates cytoplasmic accumulation of TDP-43 through Calpain-A and Importin α3
Park, J. H., Chung, C. G., Park, S. S., Lee, D., Kim, K. M., Jeong, Y., Kim, E. S., Cho, J., Jeon, Y., Shen, C.-K. J., et al. (2020) · eLife · doi:10.7554/elife.60132 · Cited by 32
FTLD-TDP assemblies seed neoaggregates with subtype-specific features via a prion-like cascade
Rossi, P. D., Lewis, A. J., Furrer, J., Vos, L. D., Demeter, T., Zbinden, A., Zhong, W., Wiersma, V. I., Scialò, C., Weber, J., et al. (2021) · EMBO Reports · doi:10.15252/embr.202153877 · Cited by 31
“FTLD-TDP subtypes represent 45% of all FTLD cases and are characterized by the accumulation and aggregation of transactive response (TAR) DNA-binding protein of 43 kDa (TDP-43) (Ling et al , 2013).”
Self-citationRNA-Binding Protein Misregulation in Microsatellite Expansion Disorders
Goodwin, M., & Swanson, M. S. (2014) · Advances in experimental medicine and biology · doi:10.1007/978-1-4939-1221-6_10 · Cited by 33
“Thus, some microsatellite expansion diseases, previously labeled as either RNA mediated or protein mediated, involve multiple pathogenic mechanisms and toxic agents (Ling et al. 2013 ).”
BackgroundNuclear Pore Dysfunction in Neurodegeneration
Spead, O., Zaepfel, B. L., & Rothstein, J. D. (2022) · Neurotherapeutics · doi:10.1007/s13311-022-01293-w · Cited by 32
“While the primary injury resulting in this aberrant degradation is theoretically different in C9ORF72 ALS and sALS (only ~10% of sALS cases harbor the C9ORF72 mutation) [74], it is possible that the initiation of ESCRT-III overactivity and subsequent loss of nucleoporins occurs via a common event.”
BackgroundInfluentialBiomarker development for C9orf72 repeat expansion in ALS
Mendez, E. F., & Sattler, R. (2014) · Brain Research · doi:10.1016/j.brainres.2014.09.041 · Cited by 34
Yang, S., Zhang, K. Y., Kariawasam, R., Bax, M., Fifita, J. A., Ooi, L., Yerbury, J. J., Nicholson, G. A., & Blair, I. P. (2015) · Neurotoxicity Research · doi:10.1007/s12640-015-9532-1 · Cited by 35
“UPS dysfunction has been hypothesised to play a role in ALS pathogenesis including the accumulation of neuronal protein aggregates (reviewed by Ling et al. 2013).”
Nucleocytoplasmic transport inC9orf72-mediated ALS/FTD
Zhang, K., Grima, J. C., Rothstein, J. D., & Lloyd, T. E. (2016) · Nucleus · doi:10.1080/19491034.2016.1172152 · Cited by 34
Neuronal biomolecular condensates and their implications in neurodegenerative diseases
Nam, J., & Gwon, Y. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1145420 · Cited by 34
“Amyotrophic lateral sclerosis–frontotemporal dementia, collectively now accounted as a spectrum disorder of ALS and FTD, is a representative research field where the phase transition from liquid to solid states of biomolecular condensates initiates the pathogenesis (Ling et al., 2013).”
BackgroundNOX-induced oxidative stress is a primary trigger of major neurodegenerative disorders
Zilberter, Y., Tabuena, D. R., & Zilberter, M. Y. (2023) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2023.102539 · Cited by 35
“Parkinson ’ s disease (PD), which is the second most common neurodegenerative disorder (Erkkinen et al., 2018) will also be discussed, along with frontotemporal dementia (FTD), a tauopathy (Yoshiyama et al., 2001; Y. Zhang et al., 2022) accounting for 10 – 20% of dementia cases and the second most common form of demen…”
BackgroundInfluentialMarkovinović, A., Martín‐Guerrero, S. M., Mórotz, G. M., Salam, S., Gómez‐Suaga, P., Paillusson, S., Greig, J., Lee, Y., Mitchell, J. C., Noble, W. J., et al. (2024) · Acta Neuropathologica Communications · doi:10.1186/s40478-024-01742-x · Cited by 34
“Although originally regarded as distinct diseases, FTD and ALS are now known to form a continuum with significant proportions of FTD patients displaying clinical features of ALS, and ALS patients showing FTD like symptoms [30].”
BackgroundCurrent developments in gene therapy for amyotrophic lateral sclerosis
Scarrott, J. M., Herranz-Martín, S., Alrafiah, A., Shaw, P. J., & Azzouz, M. (2015) · Expert Opinion on Biological Therapy · doi:10.1517/14712598.2015.1044894 · Cited by 35
“Some recent papers broadly review this topic [5,13,14].”
BackgroundCharng, W., Yamamoto, S., & Bellen, H. J. (2014) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2014.03.001 · Cited by 29
Foglieni, C., Papin, S., Salvadè, A., Afroz, T., Pinton, S., Pedrioli, G., Ulrich, G., Polymenidou, M., & Paganetti, P. (2017) · Scientific Reports · doi:10.1038/s41598-017-14459-w · Cited by 33
Self-citationClinicopathological overlap of neurodegenerative diseases: A comprehensive review
Das, S. K., Zhang, Z., & Ang, L. C. (2020) · Journal of Clinical Neuroscience · doi:10.1016/j.jocn.2020.04.088 · Cited by 33
A Systematic and Comprehensive Review on Disease-Causing Genes in Amyotrophic Lateral Sclerosis
Srinivasan, E., & Rajasekaran, R. (2020) · Journal of Molecular Neuroscience · doi:10.1007/s12031-020-01569-w · Cited by 33
Retinal Damage in Amyotrophic Lateral Sclerosis: Underlying Mechanisms
Soldatov, V. O., Kukharsky, M. S., Белых, А. Е., Sobolev, A., & Deykin, A. V. (2021) · Eye and Brain · doi:10.2147/eb.s299423 · Cited by 35
“That emphasizes the importance of impaired DNA/RNA metabolism and protein homeostasis as a factor determining the sensitivity of motor neurons to damage and, consequently, to the development of neurodegeneration.(64) At the moment, there are no direct evidence showing the association between pathogenic FUS and retinal…”
BackgroundAnoar, S., Woodling, N. S., & Niccoli, T. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.786076 · Cited by 37
Nuclear-import receptors as gatekeepers of pathological phase transitions in ALS/FTD
Khalil, B., Linsenmeier, M., Smith, C. L., Shorter, J., & Rossoll, W. (2024) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00698-1 · Cited by 33
“FUS pathology is observed in ~ 4% of familial and ~ 1% of sporadic ALS (sALS) cases, and ~ 9% of FTD cases [7, 145].”
BackgroundMitochondria: A Promising Convergent Target for the Treatment of Amyotrophic Lateral Sclerosis
Cunha‐Oliveira, T., Montezinho, L., Simões, R. F., de Carvalho, M., Ferreiro, E. B., & Silva, F. S. G. (2024) · Cells · doi:10.3390/cells13030248 · Cited by 33
de Sá, R. V., Sudrià-Lopez, E., Luna, M. C., Harschnitz, O., van den Heuvel, D. M. A., Kling, S., Vonk, D., Westeneng, H., Karst, H., Bloemenkamp, L. M., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-51676-0 · Cited by 37
VDAC1: A Key Player in the Mitochondrial Landscape of Neurodegeneration
Argueti-Ostrovsky, S., Barel, S., Kahn, J., & Israelson, A. (2024) · Biomolecules · doi:10.3390/biom15010033 · Cited by 31
“Multiple cellular deficits are implicated in both sporadic and familial ALS, including impaired proteostasis and protein aggregation [103–105], increased oxidative stress [106,107], excitotoxicity [108], and neuroinflammation [109–111].”
Verde, E. M., Secco, V., Ghezzi, A., Mandrioli, J., & Carra, S. (2025) · Cells · doi:10.3390/cells14100680 · Cited by 35
“TDP-43 shows high specificity towards UG-rich sequences of RNAs and, in the cytoplasm, can specifically target the 3 ′ untranslated regions (UTRs) of mRNAs/pre-mRNAs [17,49,56,149].”
InfluentialVernay, A., Therreau, L., Blot, B., Risson, V., Dirrig‐Grosch, S., Waegaert, R., Lequeu, T., Sellal, F., Schaeffer, L., Sadoul, R., et al. (2016) · Human Molecular Genetics · doi:10.1093/hmg/ddw182 · Cited by 35
Modelling amyotrophic lateral sclerosis in mice
Stephenson, J., & Amor, S. (2017) · Drug Discovery Today Disease Models · doi:10.1016/j.ddmod.2018.10.001 · Cited by 34
Watanabe, Y., Nakagawa, T., Akiyama, T., Nakagawa, M., Suzuki, N., Warita, H., Aoki, M., & Nakayama, K. (2020) · iScience · doi:10.1016/j.isci.2020.101491 · Cited by 30
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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