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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.
In the citing paper
“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]
In the citing paper
“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
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Mutations in FUS, an RNA Processing Protein, Cause Familial Amyotrophic Lateral Sclerosis Type 6
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Items 901–1,000 of 1,002
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“While, traditionally, FTLD and ALS were considered to be two separate disease identities, it is now thought that FTLD and ALS form one clinical continuum, in which pure forms are linked by overlapping syndromes called FTLD-MND [17].”
BackgroundInfluentialFrontotemporal Dementia and Glucose Metabolism
Garrett, L. R., & Niccoli, T. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.812222 · Cited by 20
Modeling neuromuscular diseases in zebrafish
Singh, J., & Patten, S. A. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.1054573 · Cited by 21
“TDP-43 regulates pre-mRNA splicing, mRNA stability, mRNA transport and translation (Ling et al., 2013).”
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“TDP-43 is a primarily nuclear DNA/RNA binding protein that has pleiotropic roles encompassing diverse cellular processes involved in gene expression and RNA regulation (Ling et al., 2013).”
BackgroundInfluentialNuclear pore dysfunction and disease: a complex opportunity
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“The initial molecular evidence that ALS and FTD share underlying pathological mechanisms came with the identification of ubiquitinated inclusions of the RNA-binding protein (RBP) TDP-43 in postmortem brain tissue from both ALS and FTD patients [144,149–153].”
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“Familial and sporadic forms of amyotrophic lateral sclerosis (ALS) are characterized by a progressive degeneration of upper and lower motoneurons (MNs) (Ling et al. 2013).”
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“TDP-43 functions in a series of steps in DNA/RNA processing (14).”
BackgroundPathway of 3-MCPD-induced apoptosis in human embryonic kidney cells
Ji, J., Zhu, P., Sun, C., Sun, J., An, L., Zhang, Y., & Sun, X. (2017) · The Journal of Toxicological Sciences · doi:10.2131/jts.42.43 · Cited by 21
RNA Granules and Their Role in Neurodegenerative Diseases
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TDP-43, a protein central to amyotrophic lateral sclerosis, is destabilized by tankyrase-1 and -2
McGurk, L., Rifai, O. M., & Bonini, N. M. (2020) · Journal of Cell Science · doi:10.1242/jcs.245811 · Cited by 21
“We propose that inhibition of Tnks-1/2, which regulates TDP-43 stability and neurotoxic properties, is a potential therapeutic target for ALS/FTD and related disorders.”
InfluentialNehls, J., Koppensteiner, H., Brack‐Werner, R., Floß, T., & Schindler, M. (2014) · PLoS ONE · doi:10.1371/journal.pone.0105478 · Cited by 20
“Overall, it is now accepted that TDP-43 is a global regulator of transcription and tissue-specific gene expression and TDP-43 has an important role in the development of neurodegenerative disorders called TDP-43 proteinopathies [7,9,10] (for a recent review see also [11]).”
BackgroundDeficiency of the zinc finger protein ZFP106 causes motor and sensory neurodegeneration
Joyce, P. I., Fratta, P., Landman, A. S., McGoldrick, P., Wackerhage, H., Groves, M., Busam, B. S., Galino, J., Corrochano, S., Beskina, O. A., et al. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv471 · Cited by 23
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“…hnRNP A1 and TDP-43; co-localization of mutant hnRNP A1 (p.D262V) to TDP-43 containing SGs; the role of TDP-43 in SG formation, and the localization of hnRNP A1 in SGs in stress activated cells, these experiments confirm that mutant hnRNP A1 is contained within TDP-43 positive SGs 22,39–42 .”
Irreversible inner ear damage from rock music.
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“TAR DNA-binding protein 43 (TDP-43) proteinopa-thy is a hallmark of ALS [49, 50] with TDP-43 protein aggregates recently being identified in cortical small blood vessels of sporadic ALS patients [51].”
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Rothstein, J. D., Keeley, O., Warlick, C., Miller, T. M., Ly, C. V., Glass, J. D., & Coyne, A. N. (2025) · Nature Communications · doi:10.1038/s41467-025-62482-7 · Cited by 28
“1, 2) consistent with the lack of TDP-43 pathology in SOD1 ALS 33,34 .”
Multi-phaseted problems of TDP-43 in selective neuronal vulnerability in ALS
Asakawa, K., Handa, H., & Kawakami, K. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-03792-z · Cited by 20
“In 97% of amyotrophic lateral sclerosis (ALS) cases, the most common motor neuron disease, and in 45% of frontotemporal dementia (FTD) cases [18], aggregation of TDP43 is detectable in degenerating neurons.”
BackgroundTDP43 ribonucleoprotein granules: physiologic function to pathologic aggregates
Corbet, G. A., Wheeler, J. R., Parker, R., & Weskamp, K. (2021) · RNA Biology · doi:10.1080/15476286.2021.1963099 · Cited by 21
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“Dysfunction of RBPs has recently been established as a contributing factor to neuronal pathology in neurodegenerative diseases, leading to wide scale disturbances in RNA processing and activity (Belzil et al., 2013; Ling et al., 2013; Libner et al., 2020).”
BackgroundGenç, B., Jara, J. H., Sanchez, S. S., Lagrimas, A. K. B., Gözütok, Ö., Koçak, N., Zhu, Y., & Özdi̇nler, P. H. (2021) · Gene Therapy · doi:10.1038/s41434-021-00303-4 · Cited by 19
“UCHL1 expression in CSMN with TDP-43 pathology improves soma size and the integrity of apical dendrites TDP-43 pathology is one of the most common proteinopaties observed in a large population of ALS patients [84, 85].”
Mechanistic Insight on General Protein-Binding Ability of ATP and the Impacts of Arginine Residues
Hu, G., Ou, X., & Li, J. (2022) · The Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.2c01478 · Cited by 21
Neuropathology and neuroanatomy of TDP-43 amyotrophic lateral sclerosis
Tredici, K. D., & Braak, H. (2022) · Current Opinion in Neurology · doi:10.1097/wco.0000000000001098 · Cited by 19
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 20
“cytoplasmic proteinaceous aggregates within neurons a primary pathological feature [9].”
BackgroundInfluentialAxon guidance genes modulate neurotoxicity of ALS-associated UBQLN2
Kim, S. H., Nichols, K. D., Anderson, E. N., Liu, Y., Ramesh, N., Jia, W., Kuerbis, C. J., Scalf, M., Smith, L. M., Pandey, U. B., et al. (2023) · eLife · doi:10.7554/elife.84382 · Cited by 19
“Defective protein folding and proteostatic stress are common pathogenic mechanisms linking genetically and anatomically diverse neurodegenerative diseases (Ling et al., 2013).”
BackgroundThe implications of physiological biomolecular condensates in amyotrophic lateral sclerosis
Fakim, H., & Velde, C. V. (2023) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2023.05.006 · Cited by 22
Lombardi, M., Corrado, L., Piola, B., Comi, C., Cantello, R. M., D’Alfonso, S., Mazzini, L., & Marchi, F. D. (2023) · Genes · doi:10.3390/genes14112039 · Cited by 23
“TDP-43 is a ubiquitously expressed DNA/RNA-binding protein [16] that contains two RNA recognition motifs, a nuclear localization sequence (NLS), a nuclear export signal [18], and a glycine-rich C-terminus that mediates protein–protein interactions [15,19].”
BackgroundIκB kinase phosphorylates cytoplasmic TDP-43 and promotes its proteasome degradation
Iguchi, Y., Takahashi, Y., Li, J., Araki, K., Amakusa, Y., Kawakami, Y., Kobayashi, K., Yokoi, S., & Katsuno, M. (2023) · The Journal of Cell Biology · doi:10.1083/jcb.202302048 · Cited by 20
Reverse engineering human neurodegenerative disease using pluripotent stem cell technology
Liu, Y., & Deng, W. (2015) · Brain Research · doi:10.1016/j.brainres.2015.09.023 · Cited by 23
“…alterations, defective axonal transport, excitotoxicity and local inflammation (Beers et al., 2006; Beers et al., 2008; Cozzolino et al., 2013; Fischer et al., 2011; Israelson et al., 2015; Ling et al., 2013; Magrane and Manfredi, 2009; Maragakis and Rothstein, 2006; Wong et al., 1995).”
BackgroundQin, X., Wang, G., Wang, H., Hu, Q., & Ying, Z. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv450 · Cited by 20
AAA+ Protein-Based Technologies to Counter Neurodegenerative Disease
March, Z. M., Mack, K. L., & Shorter, J. (2019) · Biophysical Journal · doi:10.1016/j.bpj.2019.03.007 · Cited by 21
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Neurodegeneration, Heterochromatin, and Double-Stranded RNA
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Horiuchi, M., Watanabe, S., Komine, O., Takahashi, E., Kaneko, K., Itohara, S., Shimada, M., Ogi, T., & Yamanaka, K. (2024) · Acta Neuropathologica Communications · doi:10.1186/s40478-024-01893-x · Cited by 22
“TDP-43 plays multiple roles in mRNA metabolism, including transcription, translation, splicing, and mRNA stabilization, through direct binding to > 6000 mRNAs [35, 49, 61].”
Mitra, J., Kodavati, M. M., Dharmalingam, P., Guerrero, E. N., Rao, K. S. J., Garruto, R. M., & Hegde, M. L. (2025) · Acta Neuropathologica Communications · doi:10.1186/s40478-025-01962-9 · Cited by 19
“TDP-43 mislocalization and aggregation are key features observed in a majority of ALS cases and approximately 40% of FTD patients [1, 58, 59].”
Dyer, M. S., Woodhouse, A., & Blizzard, C. A. (2021) · Brain Sciences · doi:10.3390/brainsci11070883 · Cited by 19
“This is consistent with other mouse models of familial ALS, namely SOD1 and FUS, which also have a loss of dendritic spines, but lack TDP-43 pathology [19,44,45].”
BackgroundResultShared brain transcriptomic signature in TDP-43 type A FTLD patients with or without GRN mutations
Pottier, C. P., Mateiu, L. M., Baker, M., DeJesus‐Hernandez, M., Vicente, C. T., Finch, N. A., Tian, S., van Blitterswijk, M., Murray, M. E., Ren, Y., et al. (2021) · Brain · doi:10.1093/brain/awab437 · Cited by 20
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Adding intrinsically disordered proteins to biological ageing clocks
Dormann, D., & Lemke, E. A. (2024) · Nature Cell Biology · doi:10.1038/s41556-024-01423-w · Cited by 23
“A specific example is superoxide dismutase 1 (SOD1), where mutations lead to misfolding and, ultimately, amyloid formation, accounting for ~2% of all amyotrophic lateral sclerosis cases 75 .”
McKeever, P. M., Sababi, A. M., Sharma, R., Xu, Z., Xiao, S., McGoldrick, P., Ketela, T., Sato, C., Moreno, D., Visanji, N. P., et al. (2025) · Cell Genomics · doi:10.1016/j.xgen.2025.101007 · Cited by 21
“8,148 Microglia highlight the distinct yet intersecting roles of APA and gene expression in regulatory mechanisms.”
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Proline/arginine dipeptide repeat polymers derail protein folding in amyotrophic lateral sclerosis
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RNA Is a Double-Edged Sword in ALS Pathogenesis
Zaepfel, B. L., & Rothstein, J. D. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.708181 · Cited by 20
“Although this strongly refutes the presence of any NMD dysfunction in C9ALS, this study corroborates that UPF1 is neuroprotective in this context (Zaepfel et al., 2021).”
BackgroundInfluentialBiochemical characterization of actin assembly mechanisms with ALS-associated profilin variants
Liu, X., Pimm, M. L., Haarer, B. K., Brawner, A. T., & Henty-Ridilla, J. L. (2022) · European Journal of Cell Biology · doi:10.1016/j.ejcb.2022.151212 · Cited by 19
The Lysosomal Trafficking Transmembrane Protein 106B Is Linked to Cell Death
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“ALS is an incurable motor neuron degenerative disease, characterized by loss of both upper and lower motor neurons (5, 6).”
BackgroundInfluentialJamet, M., Dupuis, L., & de Aguilar, J. G. (2024) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2024.1375330 · Cited by 18
“…the central nervous system (CNS) are affected by the pathological process, the situation is even more complex than previously thought, adding considerable complexity to its understanding (Ling et al., 2013; Hardiman et al., 2017; Mejzini et al., 2019; Abramzon et al., 2020; Antonioni et al., 2023).”
BackgroundRegulating translation in aging: from global to gene-specific mechanisms
Solyga, M., Majumdar, A., & Besse, F. (2024) · EMBO Reports · doi:10.1038/s44319-024-00315-2 · Cited by 23
Blair, K., Martínez-Serra, R., Gosset, P., Martín‐Guerrero, S. M., Mórotz, G. M., Atherton, J., Mitchell, J. C., Markovinović, A., & Miller, C. C. J. (2025) · Acta Neuropathologica Communications · doi:10.1186/s40478-025-01964-7 · Cited by 19
“…continuum of a broad neurodegenerative disorder with some mutant genes (e.g. TARDP encoding TAR DNA-binding protein 43; TDP43) being associated with both diseases whereas others (e.g. MAPT encoding Tau and SOD1 encoding Cu/Zn superoxide dismutase-1; SOD1) being associated with only FTD or ALS [61].”
Wannarong, T., & Ungprasert, P. (2020) · Clinical Neurology and Neurosurgery · doi:10.1016/j.clineuro.2020.106248 · Cited by 18
Insight Into Spinocerebellar Ataxia Type 31 (SCA31) From Drosophila Model
Ishiguro, T., Nagai, Y., & Ishikawa, K. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.648133 · Cited by 18
NOS1AP is a novel molecular target and critical factor in TDP-43 pathology
Cappelli, S., Spalloni, A., Feiguin, F. M., Visani, G., Šušnjar, U., Brown, A., Phatnani, H. P., Kwan, J. Y., Sareen, D., Broach, J. R., et al. (2022) · Brain Communications · doi:10.1093/braincomms/fcac242 · Cited by 17
Transthyretin attenuates TDP-43 proteinopathy by autophagy activation via ATF4 in FTLD-TDP
Chu, Y.-P., Jin, L., Wang, L., Ho, P., Wei, W., & Tsai, K. (2022) · Brain · doi:10.1093/brain/awac412 · Cited by 18
Sato, Y., Terawaki, S., Oikawa, D., Shimizu, K., Okina, Y., Ito, H., & Tokunaga, F. (2023) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2023.1089213 · Cited by 17
“The ubiquitinated insoluble cytoplasmic inclusions of TDP-43 are found in 97% of ALS and 45% of FTD cases, indicating that TDP-43 inclusions are a hallmark of ALS/FTD-mediated proteinopathy (Ling et al., 2013).”
BackgroundAlhindi, A., Shand, M., Smith, H. L., Leite, A. S., Huang, Y., van der Hoorn, D., Ridgway, Z., Faller, K. M. E., Jones, R. A., Gillingwater, T. H., et al. (2023) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12925 · Cited by 18
“FTLD-TDP and ALS are considered to be on a spectrum because of their overlapping TDP-43 pathology and clinical presentation [45], and so, although we have focussed on describing motor neuron-related pathology here, this model may also be of interest for studying other TDP-43 proteinopathies.”
Targeting Progranulin as an Immuno-Neurology Therapeutic Approach
Boylan, M. A., Pincetic, A., Romano, G. J., Tatton, N. A., Kenkare-Mitra, S., & Rosenthal, A. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242115946 · Cited by 19
“Hyperphosphorylated extranuclear inclusions of the TDP-43 protein have been implicated in FTD and ALS [7,150], AD [151,152], and LATE [153].”
BackgroundGraphene Quantum Dots Attenuate TDP-43 Proteinopathy in Amyotrophic Lateral Sclerosis
Park, N.-Y., Heo, Y., Yang, J. W., Yoo, J. M., Jang, H. J., Jo, J. H., Park, S. J., Lin, Y., Choi, J., Jeon, H., et al. (2025) · ACS Nano · doi:10.1021/acsnano.4c15283 · Cited by 20
Hedges, E. C., Mehler, V. J., & Nishimura, A. L. (2016) · Stem Cells International · doi:10.1155/2016/9279516 · Cited by 19
“Approximately 10% of ALS cases are familial (FALS), often with an autosomal dominant inheritance pattern, and the remaining 90% of cases occur sporadically (SALS) [8], many with an unknown cause.”
Energy Homeostasis and Abnormal RNA Metabolism in Amyotrophic Lateral Sclerosis
Liu, Y., Tsai, P.-Y., & Chern, Y. (2017) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2017.00126 · Cited by 17
“Many ALS genes (e.g., TDP-43, FUS/TLS, hnRNPA1, MATR3) encode RNA-binding proteins that have been found to affect multiple levels of RNA processing, including mRNA transcription, RNA transport, mRNA stabilization and miRNA biogenesis (Ling et al., 2013; Taylor et al., 2016).”
BackgroundDrosophila models of amyotrophic lateral sclerosis with defects in RNA metabolism
Zhang, K., Coyne, A. N., & Lloyd, T. E. (2018) · Brain Research · doi:10.1016/j.brainres.2018.04.043 · Cited by 21
Dash, B. P., Naumann, M., Sterneckert, J. L., & Hermann, A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21186938 · Cited by 19
Sears, J. C., & Broadie, K. S. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.108266 · Cited by 18
“Indeed, several neural cytosolic aggregation diseases are linked to “prion-like” domain mutations (Ling et al., 2013).”
BackgroundCheng, F., Luca, A. D., Hogan, A. L., Rayner, S. L., Davidson, J. M., Watchon, M., Stevens, C. H., Muñoz, S. S., Ooi, L., Yerbury, J. J., et al. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.627740 · Cited by 17
Adiutori, R., Puentes, F., Bremang, M., Lombardi, V., Zubiri, I., Leoni, E., Aarum, J., Sheer, D., McArthur, S., Pike, I., et al. (2021) · Brain Communications · doi:10.1093/braincomms/fcab148 · Cited by 19
“CPAs obtained from individuals with ALS include products of translation of ALS risk genes such as FUS and SOD1 (Table 1) and a large number of proteins implicated in the proteasome system, an essential clearance mechanism of defective proteins.(59,60) Plasma CPAs and specifically low concentration ALS CPAs, affect bot…”
BackgroundLee, S., & Levin, M. C. (2014) · F1000Research · doi:10.12688/f1000research.4436.1 · Cited by 18
Simple animal models for amyotrophic lateral sclerosis drug discovery
Patten, S. A., Parker, J. A., Wen, X., & Drapeau, P. (2016) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2016.1196183 · Cited by 20
“These mutations are mostly clustered at the C-terminus, at a predicted nuclear localization signal [16].”
BackgroundTejwani, L., Jung, Y., Kokubu, H., Sowmithra, S., Ni, L., Lee, C., Sanders, B., Lee, P. J., Xiang, Y., Luttik, K., et al. (2023) · Journal of Clinical Investigation · doi:10.1172/jci138207 · Cited by 17
“patients with sporadic ALS (sALS) or familial ALS (fALS) (1-3), as well as in subsets of patients 24 with frontotemporal dementia (FTD) (1, 3), Alzheimer’s disease (4), and Parkinson’s disease (5).”
BackgroundMicroRNAs in ALS: small pieces to the puzzle
Bicker, S., & Schratt, G. M. (2015) · The EMBO Journal · doi:10.15252/embj.201592805 · Cited by 17
“Importantly, mutations in several genes encoding RNA-binding proteins (RBPs), such as TAR DNA-binding protein 43 (TDP-43) or fused in sarcoma (FUS), have been linked to this pathology (Ling et al , 2013).”
Regulation of Endoplasmic Reticulum–Mitochondria Tethering and Ca2+ Fluxes by TDP-43 via GSK3β
Peggion, C., Massimino, M. L., Bonadio, R. S., Lia, F., Lopreiato, R., Cagnin, S., Calí, T., & Bertoli, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222111853 · Cited by 19
Loss of PML nuclear bodies in familial amyotrophic lateral sclerosis-frontotemporal dementia
Antoniani, F., Cimino, M., Mediani, L., Vinet, J., Verde, E. M., Secco, V., Yamoah, A., Tripathi, P., Aronica, E., Cicardi, M. E., et al. (2023) · Cell Death Discovery · doi:10.1038/s41420-023-01547-2 · Cited by 19
“The expansion of the GGGGCC (G 4 C 2 ) hexanucleotide repeat in the fi rst intron of the C9ORF72 gene is one of the most frequent genetic causes of ALS and FTD [2].”
Epigenetics in Neurodegenerative Diseases
van Zundert, B., & Montecino, M. A. (2025) · Sub-cellular biochemistry/Subcellular biochemistry · doi:10.1007/978-3-031-75980-2_3 · Cited by 18
Evaluating noncoding nucleotide repeat expansions in amyotrophic lateral sclerosis
Figley, M. D., Thomas, A., & Gitler, A. D. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.09.024 · Cited by 17
Cognitive impairment in amyotrophic lateral sclerosis, clues from the SOD1 mouse
Spalloni, A., & Longone, P. (2015) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2015.11.006 · Cited by 19
Multimodal MRI quantification of the common neurostructural bases within the FTD-ALS continuum
Crespi, C., Dodich, A., Cappa, S. F., Canessa, N., Iannaccone, S., Corbo, M., Lunetta, C., Falini, A., & Cerami, C. (2017) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2017.09.019 · Cited by 17
“The Frontotemporal Dementia (FTD) – Amyotrophic Later l Sclerosis (ALS) continuum hypothesis, considering FTD and ALS as extreme points of a disease spectrum, is now supported by a robust genetic and neuropathological evidence (Ferrari et al., 2011; Ling et al., 2013).”
BackgroundAls and Ftd: Insights into the disease mechanisms and therapeutic targets
Liščić, R. M. (2017) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2017.10.012 · Cited by 17
“The most affected molecular species is pre-mRNA (Ling et al., 2013).”
BackgroundKasu, Y. A. T., Alemu, S., Lamari, A., Loew, N., & Brower, C. S. (2018) · Molecular and Cellular Biology · doi:10.1128/mcb.00243-18 · Cited by 17
Cha, S. J., Choi, H., Kim, H. ‐., Choi, E. J., Song, K., Im, D. S., & Kim, K. (2019) · Insect Molecular Biology · doi:10.1111/imb.12608 · Cited by 19
“Particularly, FUS is aDNA/RNA-binding protein that is implicated inRNAmetabolism, includingRNAprocessing, splicing, transport and translation, by regulating cellular localization and degradation (Lagier-Tourenne et al., 2010; Ling et al., 2013; Kapeli et al., 2016).”
BackgroundTrends in Understanding the Pathological Roles of TDP-43 and FUS Proteins
Buratti, E. (2021) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-51140-1_15 · Cited by 19
Disease Mechanisms and Therapeutic Approaches in C9orf72 ALS-FTD
Mayl, K., Shaw, C. E., & Lee, Y. (2021) · Biomedicines · doi:10.3390/biomedicines9060601 · Cited by 18
“Nonetheless, this overlap of C9ALS-FTD with other forms of the disease may reflect a common point of convergence across the disease spectrum [26].”
BackgroundKrause, K., Wulf, M., Sommer, P., Barkovits, K., Vorgerd, M., Marcus, K., & Eggers, B. (2021) · Diagnostics · doi:10.3390/diagnostics11091522 · Cited by 17
Tsai, Y.-L., Mu, Y. C., & Manley, J. L. (2022) · Scientific Reports · doi:10.1038/s41598-022-12098-4 · Cited by 17
Henriques, A., Kastner, S., Chatzikonstantinou, E., Pitzer, C., Plaas, C., Kirsch, F., Wafzig, O., ger, C. K. ⁄., Spoelgen, R., de Aguilar, J. G., et al. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00464 · Cited by 17
“ALS patients present pathological inclusion of TDP-43 and FUS, two proteins that closely interact with RNA metabolism (Ling et al., 2013).”
BackgroundhnRNPA2/B1 Function in Neurodegeneration: It’s a Gain, Not a Loss
Hutten, S., & Dormann, D. (2016) · Neuron · doi:10.1016/j.neuron.2016.11.014 · Cited by 17
“…commonly altered AS events and examine whether they are indeed consistently altered in individuals with different ALS/MSP-associated gene mutations (Ling et al., 2013) and which other common changes on the mRNA and protein level occur in different ALS/MSP-linked mutants, as they may be relevant to…”
BackgroundPorterfield, V. M., Khan, S. S., Foff, E. P., Köseoğlu, M. M., Blanco, I. K., Jayaraman, S., Lien, E. L., McConnell, M. J., Bloom, G. S., Lazo, J. S., et al. (2020) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2020.02.011 · Cited by 18
“Given that ALS patients can present with FTD symptoms (Ling et al., 2013; Ng et al., 2015) and C9orf72 has been found in other neurodegenerative disorders, such as Alzheimer’s disease, we wanted to establish a relevant cell culture model that more accurately reflected the areas of the ALS/FTD brain affected by neurode…”
BackgroundShort RNA chaperones promote aggregation-resistant TDP-43 conformers to mitigate neurodegeneration
Copley, K. E., Mauna, J. C., Danielson, H. L., Chen, Q., Ozguney, B., Ngo, M., Xie, L., Smirnov, A., Davis, M., Mayne, L., et al. (2026) · Science · doi:10.1126/science.adv3301 · Cited by 16
Genetic evidence for the liver-brain axis: lipid metabolism and neurodegenerative disease risk
Wang, Z., Yin, Z., Sun, G., Zhang, D., & Zhang, J. (2025) · Lipids in Health and Disease · doi:10.1186/s12944-025-02455-3 · Cited by 16
“The pathogenesis of ALS involves multiple biological processes, including protein misfolding, neuroinflammation, oxidative stress, and metabolic imbalance [33–35].”
Quezada, E. R., Cappelli, C., Díaz, I. D. P., Jury, N., Wightman, N., Brown, R. H., Montecino, M. A., & van Zundert, B. (2021) · Clinical Epigenetics · doi:10.1186/s13148-021-01039-z · Cited by 17
Ueda, T., Ito, T., Inden, M., Kurita, H., Yamamoto, A., & Hozumi, I. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.805379 · Cited by 16
Cortical Hyperexcitability in the Driver’s Seat in ALS
Gunes, Z. I., Kan, V. W. Y., Jiang, S., Logunov, E., Ye, X., & Liebscher, S. (2022) · Clinical and Translational Neuroscience · doi:10.3390/ctn6010005 · Cited by 18
“In addition to intrinsic alterations of UMNs, there is also evidence for an augmented synaptic input onto them, witnessed as increased miniature excitatory synaptic current (mEPSC) frequencies in UMNs in presymptomatic SOD1G93A [103] and in TDP-43Q331K tg mice [104].”
BackgroundInfluentialShenoy, J., Lends, A., Berbon, M., Abdul-Shukkoor, M. B., Mammeri, N. E., Bertoni, M., Saad, A., Morvan, E., Grélard, A., Lecomte, S., et al. (2023) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2023.1148302 · Cited by 19
“About 90% of ALS patients and about 50% of FTLD patients are observed with ubiquitinated TDP43 neuronal inclusion (Ling et al., 2013; Tan et al., 2017).”
BackgroundAnzilotti, S., Valente, V., Brancaccio, P., Franco, C., Casamassa, A., Lombardi, G., Palazzi, A., Conte, A., Paladino, S., Canzoniero, L. M. T., et al. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.115503 · Cited by 16
Zibold, J., Lessard, L., Picard, F., da Silva, L. A. G., Zadorozhna, Y., Streichenberger, N., Belotti, E., Osseni, A., Emerit, A., Errazuriz-Cerda, E., et al. (2023) · Brain · doi:10.1093/brain/awad410 · Cited by 16
Inorganic polyphosphate: from basic research to diagnostic and therapeutic opportunities in ALS/FTD
Garcés, P., Amaro, A., Montecino, M. A., & van Zundert, B. (2024) · Biochemical Society Transactions · doi:10.1042/bst20230257 · Cited by 14
Koike, Y. M. (2024) · Neuroscience Research · doi:10.1016/j.neures.2024.05.001 · Cited by 17
“Nuclear depletion and cytoplasmic aggregation of TDP-43 are pathological features found in more than 97% of ALS cases and in nearly 50% of FTD cases (known as FTLD-TDP) (Taylor et al., 2016) (Ling et al., 2013).”
BackgroundMitigation of TDP-43 toxic phenotype by an RGNEF fragment in amyotrophic lateral sclerosis models
Droppelmann, C. A., Campos‐Melo, D., Noches, V., McLellan, C., Szabla, R., Lyons, T. A., Amzil, H., Withers, B., Kaplanis, B., Sonkar, K. S., et al. (2024) · Brain · doi:10.1093/brain/awae078 · Cited by 15
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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