The DOI matches its Crossref record; 259 of the 260 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
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
Flagged first, then by citations
1 of the 260 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Zhang, Y., Chen, K., Sloan, S. A., Bennett, M. L., Scholze, A. R., O'Keeffe, S., Phatnani, H. P., Guarnieri, P., Caneda, C., Ruderisch, N., et al. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.1860-14.2014 · Cited by 4,875
“Rather, it is a disease of the spinal cord in which astrocytes, microglia, and oligodendrocytes all contribute to disease progression (Ling et al., 2013).”
BackgroundHallmarks of neurodegenerative diseases
Wilson, D. M., Cookson, M. R., Van Den Bosch, L., Zetterberg, H., Holtzman, D. M., & Dewachter, I. (2023) · Cell · doi:10.1016/j.cell.2022.12.032 · Cited by 1,789
“19,54,56,57,200,201,203,205,208 Defects in RNA metabolism/ homeostasis lead to defects in RNA driven processes and RNA transport, as well as to the formation of characteristic stress granules (SGs) that involve ribonucleoproteins (RNPs).”
InfluentialPrinciples and Properties of Stress Granules
Protter, D. S. W., & Parker, R. (2016) · Trends in Cell Biology · doi:10.1016/j.tcb.2016.05.004 · Cited by 1,738
Alternative polyadenylation of mRNA precursors
Tian, B., & Manley, J. L. (2017) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2016.116 · Cited by 1,179
Scotti, M. M., & Swanson, M. S. (2016) · Nature Reviews Genetics · doi:10.1038/nrg.2015.3 · Cited by 1,163
Burke, K. A., Janke, A. M., Rhine, C. L., & Fawzi, N. L. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.09.006 · Cited by 932
“mutations located within the regions coding for FUS LC are linked to ALS (Belzil et al., 2009; Cruts et al., 2012; Ling et al., 2013; Ticozzi et al., 2009), including G156E, which increases FUS aggregation propensity in vitro and in cell culture (Nomura et al.”
InfluentialConicella, A. E., Zerze, G. H., Mittal, J., & Fawzi, N. L. (2016) · Structure · doi:10.1016/j.str.2016.07.007 · Cited by 881
Antisense oligonucleotides: the next frontier for treatment of neurological disorders
Rinaldi, C., & Wood, M. J. A. (2018) · Nature Reviews Neurology · doi:10.1038/nrneurol.2017.148 · Cited by 788
Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis
Prasad, A., Bharathi, V., Sivalingam, V., Girdhar, A., & Patel, B. K. (2019) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2019.00025 · Cited by 817
“TDP-43-RNA Interactions TDP-43 has versatile functions and it is involved in several steps of RNA metabolism such as: transcription, translation, mRNA transport, mRNA stabilization, microRNA (miRNA) and long non-coding RNA (lncRNA) processing etc. (Ling et al., 2013; Coyne et al., 2017) (Figure 3).”
BackgroundC9orf72-mediated ALS and FTD: multiple pathways to disease
Balendra, R., & Isaacs, A. M. (2018) · Nature Reviews Neurology · doi:10.1038/s41582-018-0047-2 · Cited by 715
TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD
Ling, J. P., Pletniková, O., Troncoso, J. C., & Wong, P. C. (2015) · Science · doi:10.1126/science.aab0983 · Cited by 697
ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair
Klim, J. R., Williams, L. A., Limone, F., Guerra San Juan, I., Davis-Dusenbery, B. N., Mordes, D. A., Burberry, A., Steinbaugh, M. J., Gamage, K. K., Kirchner, R., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-018-0300-4 · Cited by 653
Phase Separation of FUS Is Suppressed by Its Nuclear Import Receptor and Arginine Methylation
Hofweber, M., Hutten, S., Bourgeois, B. M. R., Spreitzer, E., Niedner, A., Schifferer, M., Ruepp, M., Simons, M., Niessing, D., Madl, T., et al. (2018) · Cell · doi:10.1016/j.cell.2018.03.004 · Cited by 654
“RBP aggregation is thought to cause widespread disturbances in neuronal RNA metabolism and neurodegeneration, by loss- and/or gain-of-function mechanisms (Ling et al., 2013).”
Preclinical research: Make mouse studies work
Perrin, S. (2014) · Nature · doi:10.1038/507423a · Cited by 668
Melamed, Z., López-Erauskin, J., Baughn, M. W., Zhang, O., Drenner, K., Sun, Y., Freyermuth, F., McMahon, M. A., Beccari, M. S., Artates, J. W., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-018-0293-z · Cited by 635
Self-citationTDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD
Chou, C., Zhang, Y., Umoh, M. E., Vaughan, S. W., Lorenzini, I., Liu, F., Sayegh, M., Donlin-Asp, P., Chen, Y. H., Duong, D. M., et al. (2018) · Nature Neuroscience · doi:10.1038/s41593-017-0047-3 · Cited by 606
“Our study provides evidence that (1) proteins involved in nucleocytoplasmic transport are major components of pathological TDP-43 aggregates; (2) aggregated and mutant TDP-43 cause cytoplasmic mislocalization and/or aggregation of Nups and TFs; (3) PrLDs present in human Nups containing FG repeats are required and suf…”
BackgroundMethodInfluentialTherapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice
Becker, L. A., Huang, B., Bieri, G., Ma, R., Knowles, D. A., Jafar-Nejad, P., Messing, J., Kim, H. J., Soriano, A., Auburger, G., et al. (2017) · Nature · doi:10.1038/nature22038 · Cited by 571
“Reduction of ataxin 2 has exciting therapeutic potential for ALS and FTD because TDP-43 pathology is a component of 97% of ALS cases and nearly 50% of FTD cases 6 .”
InfluentialLagier‐Tourenne, C., Baughn, M. W., Rigo, F., Sun, S., Liu, P., Li, H., Jiang, J., Watt, A. T., Chun, S. J., Katz, M., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1318835110 · Cited by 585
“The extent of hexanucleotide-containing RNA foci in tissues of the CNS was determined by FISH for 3 C9orf72 ALS or ALS/FTD nervous systems and 25 nervous systems not carrying a C9orf72 abnormal expansion (SI Appendix, Table 2).”
BackgroundInfluentialSelf-citationJiang, J., Zhu, Q., Gendron, T. F., Saberi, S., McAlonis-Downes, M., Seelman, A., Stauffer, J. E., Jafar-nejad, P., Drenner, K., Schulte, D., et al. (2016) · Neuron · doi:10.1016/j.neuron.2016.04.006 · Cited by 536
“Neuron 90, 535–550, May 4, 2016 ª2016 Elsevier Inc. 535 Proposed mechanisms by which C9ORF72 repeat expansions cause disease (referred to as C9ALS/FTD) include loss of C9ORF72 protein function and gain of toxicity (Gendron et al., 2014; Ling et al., 2013).”
Self-citationRegulation of lipid peroxidation and ferroptosis in diverse species
Conrad, M., Kagan, V. E., Bayir, H., Pagnussat, G. C., Head, B., Traber, M. G., & Stockwell, B. R. (2018) · Genes & Development · doi:10.1101/gad.314674.118 · Cited by 544
“The combination of 16-86 (a derivative of ferrostatin-1), necrostatin-1, and Sanglifehrin A proved to be highly protective in a mouse model of transient IR injury (IRI) in the kidney (Linkermann et al. 2014).”
BackgroundRNA Binding Antagonizes Neurotoxic Phase Transitions of TDP-43
Mann, J. R., Gleixner, A. M., Mauna, J. C., Gomes, E., DeChellis-Marks, M. R., Needham, P. G., Copley, K. E., Hurtle, B. T., Portz, B., Pyles, N. J., et al. (2019) · Neuron · doi:10.1016/j.neuron.2019.01.048 · Cited by 547
“No effective treatments currently exist to halt ALS or FTD progression, and the cause(s) of these disorders remain unknown.”
InfluentialAmyotrophic lateral sclerosis—a model of corticofugal axonal spread
Braak, H., Brettschneider, J., Ludolph, A. C., Lee, V. M., Trojanowski, J. Q., & Tredici, K. D. (2013) · Nature Reviews Neurology · doi:10.1038/nrneurol.2013.221 · Cited by 544
Gasset-Rosa, F., Lu, S., Yu, H., Chen, C., Melamed, Z., Guo, L. E., Shorter, J., Cruz, S. D., & Cleveland, D. W. (2019) · Neuron · doi:10.1016/j.neuron.2019.02.038 · Cited by 526
“These two progressive neurodegenerative diseases, which share genetic and pathological features (Ling et al., 2013), are without effective treatments to slow fatal disease progression (Taylor et al.”
Self-citationMead, R. J., Shan, N., Reiser, H. J., Marshall, F., & Shaw, P. J. (2023) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00612-2 · Cited by 505
Phase separation and neurodegenerative diseases: a disturbance in the force
Zbinden, A., Pérez-Berlanga, M., De Rossi, P., & Polymenidou, M. (2020) · Developmental Cell · doi:10.1016/j.devcel.2020.09.014 · Cited by 500
Self-citationThere's Something Wrong with my MAM; the ER–Mitochondria Axis and Neurodegenerative Diseases
Paillusson, S., Stoica, R., Gomez-Suaga, P., Lau, D. H. W., Mueller, S., Miller, T., & Miller, C. C. J. (2016) · Trends in Neurosciences · doi:10.1016/j.tins.2016.01.008 · Cited by 439
“Moreover, ALS is now known to be clinically, pathologically, and genetically linked to FTD, which is the second most-common form of presenile dementia after AD [1].”
BackgroundInfluentialOsaki, T., Uzel, S. G. M., & Kamm, R. D. (2018) · Science Advances · doi:10.1126/sciadv.aat5847 · Cited by 429
RNA-binding proteins with prion-like domains in health and disease
Harrison, A. F., & Shorter, J. (2017) · Biochemical Journal · doi:10.1042/bcj20160499 · Cited by 431
“Similar to TDP-43 in many ways, FUS, also sometimes known as translocated in liposarcoma (TLS), is a primarily nuclear protein that functions in transcriptional regulation, pre-mRNA splicing, and other elements of mRNA processing and metabolism [56,82].”
InfluentialEmerging insights into the complex genetics and pathophysiology of amyotrophic lateral sclerosis
Goutman, S. A., Hardiman, O. M., Al‐Chalabi, A., Chiò, A., Savelieff, M. G., Kiernan, M. C., & Feldman, E. L. (2022) · The Lancet Neurology · doi:10.1016/s1474-4422(21)00414-2 · Cited by 429
Physiological functions and pathobiology of TDP ‐43 and FUS / TLS proteins
Ratti, A., & Buratti, E. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13625 · Cited by 417
Frontotemporal dementia and its subtypes: a genome-wide association study
Ferrari, R., Hernandez, D. G., Nalls, M. A., Rohrer, J. D., Ramasamy, A., Kwok, J. B. J., Dobson-Stone, C., Brooks, W. S., Schofield, P. R., Halliday, G. M., et al. (2014) · The Lancet Neurology · doi:10.1016/s1474-4422(14)70065-1 · Cited by 383
Exosome secretion is a key pathway for clearance of pathological TDP-43
Iguchi, Y., Eid, L., Parent, M., Soucy, G., Bareil, C., Riku, Y., Kawai, K., Takagi, S., Yoshida, M., Katsuno, M., et al. (2016) · Brain · doi:10.1093/brain/aww237 · Cited by 360
“The paradigm of prion-like propagation has been speculated as the cause of the spreading as well as other neurodegenerative diseases such as Alzheimer’s disease or Parkinson’s disease (Ling et al., 2013; Falsone and Falsone, 2015; Maniecka and Polymenidou, 2015).”
BackgroundKim, H., Raphael, A. R., LaDow, E., McGurk, L., Weber, R. A., Trojanowski, J. Q., Lee, V. M. ‐., Finkbeiner, S. M., Gitler, A. D., & Bonini, N. M. (2013) · Nature Genetics · doi:10.1038/ng.2853 · Cited by 383
“Because of the importance of RNA metabolic processes in ALS pathogenesis 36 and the enrichment of RNA-binding proteins as modifiers, we performed a network analysis of the identified RNA-binding proteins, defining genetic and physical interactions between hits and additional genes that interacted…”
C9orf72 BAC Mouse Model with Motor Deficits and Neurodegenerative Features of ALS/FTD
Liu, Y., Pattamatta, A., Zu, T., Reid, T. S., Bardhi, O., Borchelt, D., Yachnis, A. T., & Ranum, L. P. W. (2016) · Neuron · doi:10.1016/j.neuron.2016.04.005 · Cited by 368
“TDP-43 inclusions are a neuropathological feature found in >90% of ALS and 50% of FTD autopsy cases, including C9orf72 ALS/FTD (Ling et al., 2013).”
The role of FUS gene variants in neurodegenerative diseases
Deng, H., Gao, K., & Jankovic, J. J. (2014) · Nature Reviews Neurology · doi:10.1038/nrneurol.2014.78 · Cited by 371
Neurodegenerative Diseases: Expanding the Prion Concept
Walker, L. C., & Jucker, M. (2015) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-071714-033828 · Cited by 361
“…ALS and FTD, the lesions appear to spread systematically among brain regions (Braak et al. 2013, Brettschneider et al. 2014, Ravits & La Spada 2009), suggestive of the transport of a prion-like agent (Braak et al. 2013, Cushman et al. 2010, Grad & Cashman 2014, Ling et al. 2013, Udan & Baloh 2011).”
BackgroundTDP-43 Proteinopathy and ALS: Insights into Disease Mechanisms and Therapeutic Targets
Scotter, E. L., Chen, H.-J., & Shaw, C. E. (2015) · Neurotherapeutics · doi:10.1007/s13311-015-0338-x · Cited by 382
“Despite this diverse etiology of disease, 97 % of patients display a common phenotype in diseaseaffected tissues, namely the deposition of the TAR-DNA binding protein (TDP)-43 [1, 2].”
HSP70 chaperones RNA-free TDP-43 into anisotropic intranuclear liquid spherical shells
Yu, H., Lu, S., Gasior, K. I., Singh, D., Tapia, O., Vazquez‐Sanchez, S., Toprani, D., Beccari, M. S., Yates, J. R., Cruz, S. D., et al. (2021) · Science · doi:10.1126/science.abb4309 · Cited by 347
Self-citationAfroz, T., Hock, E., Erñst, P., Foglieni, C., Jambeau, M., Gilhespy, L. A. B., Laferrière, F., Maniecka, Z., Plückthun, A., Mittl, P. R. E., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-00062-0 · Cited by 358
Self-citationThe neurogenetics of alternative splicing
Vuong, C. K., Black, D. L., & Zheng, S. (2016) · Nature Reviews Neuroscience · doi:10.1038/nrn.2016.27 · Cited by 340
VCP/p97 cooperates with YOD1, UBXD1 and PLAA to drive clearance of ruptured lysosomes by autophagy
Papadopoulos, C., Kirchner, P., Bug, M., Grum, D., Koerver, L., Schulze, N., Pöhler, R., Dressler, A., Fengler, S., Arhzaouy, K., et al. (2016) · The EMBO Journal · doi:10.15252/embj.201695148 · Cited by 353
“The fact that p97 clears damaged lysosomes and also responds to the tau-induced lysosomal damage adds an unanticipated aspect to the emerging picture of p97 as a critical modulator of neurodegeneration (Rubinsztein, 2006; Ling et al , 2013).”
Oligodendroglia: metabolic supporters of neurons
Philips, T., & Rothstein, J. D. (2017) · Journal of Clinical Investigation · doi:10.1172/jci90610 · Cited by 379
“103 , 104).”
Phase Separation: Linking Cellular Compartmentalization to Disease
Aguzzi, A., & Altmeyer, M. (2016) · Trends in Cell Biology · doi:10.1016/j.tcb.2016.03.004 · Cited by 343
“Given that many of the IDPs involved in dynamic phase transitions, including the FET protein family and several hnRNPs, as well as the machineries involved in stress granule clearance, are frequently mutated in proteinopathies and form pathological aggregates (Figure 2 and Table 1), we may think of protein amyloids as…”
BackgroundWalker, A. K., Spiller, K. J., Ge, G., Zheng, A., Xu, Y., Zhou, M. S., Tripathy, K., Kwong, L. K., Trojanowski, J. Q., & Lee, V. M. ‐. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1460-x · Cited by 343
“Moreover, many of these animals do not develop a progressive ALS-like phenotype, which is a requirement for future preclinical testing of ALS therapeutics [29].”
FUS and TDP-43 Phases in Health and Disease
Portz, B., Lee, B. L., & Shorter, J. (2021) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2020.12.005 · Cited by 335
“Thus, ALS and FTD cases with FUS inclusions lack TDP-43 inclusions, and vice versa [45].”
BackgroundMurphy, S. E., & Levine, T. P. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2016.02.009 · Cited by 328
Drosophila as an In Vivo Model for Human Neurodegenerative Disease
McGurk, L., Berson, A., & Bonini, N. M. (2015) · Genetics · doi:10.1534/genetics.115.179457 · Cited by 333
“have led to an explosion in the identification of genes associated with ALS (Ling et al. 2013; Renton et al. 2014).”
BackgroundAmyotrophic Lateral Sclerosis: An Update for 2018
Oskarsson, B., Gendron, T. F., & Staff, N. P. (2018) · Mayo Clinic Proceedings · doi:10.1016/j.mayocp.2018.04.007 · Cited by 338
Sequential distribution of pTDP-43 pathology in behavioral variant frontotemporal dementia (bvFTD)
Brettschneider, J., Tredici, K. D., Irwin, D. J., Grossman, M., Robinson, J. L., Toledo, J. B., Fang, L., Deerlin, V. M. V., Ludolph, A. C., Lee, V. M. ‐., et al. (2014) · Acta Neuropathologica · doi:10.1007/s00401-013-1238-y · Cited by 328
“This was reinforced shortly thereafter by the discovery of mutations in the TARDBP gene encoding TDP-43 that cause FTLD-TDP and/or ALS (reviewed in [63]).”
BackgroundSullivan, P. M., Zhou, X., Robins, A. M., Paushter, D. H., Kim, D., Smolka, M. B., & Hu, F. (2016) · Acta Neuropathologica Communications · doi:10.1186/s40478-016-0324-5 · Cited by 295
“are considered two manifestations of a continuous disease spectrum [1, 7, 15, 29, 30, 49].”
BackgroundMoloney, E. B., de Winter, F., & Verhaagen, J. (2014) · Frontiers in Neuroscience · doi:10.3389/fnins.2014.00252 · Cited by 319
“…neurons, misfolded mutant SOD1 protein preferentially binds to mitochondrial membranes (Vande Velde et al., 2008) and accumulation of SOD1 mutations in mitochondria leads to organelle dysfunction, oxidative stress and subsequent defects in neuronal physiology (Liu et al., 2004; Deng et al., 2006).”
BackgroundALS Genes in the Genomic Era and their Implications for FTD
Nguyen, H. P., Broeckhoven, C. V., & van der Zee, J. (2018) · Trends in Genetics · doi:10.1016/j.tig.2018.03.001 · Cited by 314
APOE2: protective mechanism and therapeutic implications for Alzheimer’s disease
Li, Z., Shue, F., Zhao, N., Shinohara, M., & Bu, G. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00413-4 · Cited by 306
“The impact of APOE*ε2 on FTLD risk remains inconclusive, with APOE*ε2 exerting either no effect or an increased risk of FTLD [256–258].”
BackgroundInfluentialFang, M. Y., Markmiller, S., Vu, A. Q., Javaherian, A., Dowdle, W. E., Jolivet, P., Bushway, P., Castello, N. A., Baral, A., Chan, M. Y., et al. (2019) · Neuron · doi:10.1016/j.neuron.2019.05.048 · Cited by 294
Reducing the RNA binding protein TIA1 protects against tau-mediated neurodegeneration in vivo
Apicco, D. J., Ash, P. E. A., Maziuk, B., LeBlang, C., Medalla, M., Al Abdullatif, A., Ferragud, A., Botelho, E., Ballance, H. I., Dhawan, U., et al. (2018) · Nature Neuroscience · doi:10.1038/s41593-017-0022-z · Cited by 281
“RBPs such as TIA1 have multiple roles in the cell, regulating RNA localization and utilization in the soma and dendritic arbor, and processes such as splicing and RNA polymerase procession in the nucleus 43, 44 .”
TDP-43 induces mitochondrial damage and activates the mitochondrial unfolded protein response
Wang, P., Deng, J., Dong, J., Liu, J., Bigio, E. H., Mesulam, M. M., Wang, T., Sun, L., Wang, L., Lee, A. Y., et al. (2019) · PLoS Genetics · doi:10.1371/journal.pgen.1007947 · Cited by 296
Conlon, E. G., Lü, L., Sharma, A., Yamazaki, T., Tang, T. K. K., Shneider, N. A., & Manley, J. L. (2016) · eLife · doi:10.7554/elife.17820 · Cited by 277
TDP-43 pathology and neuronal loss in amyotrophic lateral sclerosis spinal cord
Brettschneider, J., Arai, K., Tredici, K. D., Toledo, J. B., Robinson, J. L., Lee, E. B., Kuwabara, S., Shibuya, K., Irwin, D. J., Fang, L., et al. (2014) · Acta Neuropathologica · doi:10.1007/s00401-014-1299-6 · Cited by 279
“TDP-43 is a highly conserved and widely expressed 414 amino acid proteins that are involved in splicing of pre-mrNA, transcriptional repression, microrNA synthesis, and in maintaining mrNA stability and nuclearcytoplasmic shuttling [34, 37].”
Kim, H. J., & Taylor, J. P. (2017) · Neuron · doi:10.1016/j.neuron.2017.07.029 · Cited by 280
Antisense oligonucleotides: translation from mouse models to human neurodegenerative diseases
Schoch, K. M., & Miller, T. M. (2017) · Neuron · doi:10.1016/j.neuron.2017.04.010 · Cited by 274
Triad of TDP43 control in neurodegeneration: autoregulation, localization and aggregation
Tziortzouda, P., Bosch, L. V. D., & Hirth, F. (2021) · Nature reviews. Neuroscience · doi:10.1038/s41583-021-00431-1 · Cited by 285
Truncated stathmin-2 is a marker of TDP-43 pathology in frontotemporal dementia
Prudencio, M., Humphrey, J., Pickles, S., Brown, A.-L., Hill, S. E., Kachergus, J. M., Shi, J., Heckman, M. G., Spiegel, M. R., Cook, C., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci139741 · Cited by 231
“org Volume 130 Number 11 November 2020 Introduction Tar DNA-binding protein 43 (TDP-43) regulates multiple aspects of RNA metabolism, including RNA stabilization, transcription, splicing, and transport (1).”
BackgroundDrosophila screen connects nuclear transport genes to DPR pathology in c9ALS/FTD
Boeynaems, S., Bogaert, E., Michiels, E., Gijselinck, I., Sieben, A., Jovičić, A., De Baets, G., Scheveneels, W., Steyaert, J., Cuijt, I., et al. (2016) · Scientific Reports · doi:10.1038/srep20877 · Cited by 262
Role of Microglia in Neurological Disorders and Their Potentials as a Therapeutic Target
Du, L., Zhang, Y., Chen, Y., Zhu, J., Yang, Y., & Zhang, H.-L. (2016) · Molecular Neurobiology · doi:10.1007/s12035-016-0245-0 · Cited by 280
The Src/c-Abl pathway is a potential therapeutic target in amyotrophic lateral sclerosis
Imamura, K., Izumi, Y., Watanabe, A., Tsukita, K., Woltjen, K., Yamamoto, T., Hotta, A., Kondo, T., Kitaoka, S., Ohta, A., et al. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aaf3962 · Cited by 263
“INTRODUCTION Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that causes progressive loss of motor neurons (1, 2).”
BackgroundLüscher, B., Bütepage, M., Eckei, L., Krieg, S., Verheugd, P., & Shilton, B. H. (2017) · Chemical Reviews · doi:10.1021/acs.chemrev.7b00122 · Cited by 264
Atomic structures of TDP-43 LCD segments and insights into reversible or pathogenic aggregation
Guenther, E. L., Cao, Q., Trinh, H., Lu, J., Sawaya, M. R., Cascio, D., Boyer, D. R., Rodríguez, J. A., Hughes, M. P., & Eisenberg, D. S. (2018) · Nature Structural & Molecular Biology · doi:10.1038/s41594-018-0064-2 · Cited by 254
Aulas, A., & Velde, C. V. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00423 · Cited by 263
“In contrast, FUS-immunoreactive inclusions are found in only 2% of ALS and 9% of FTD cases (Arai et al., 2006; Neumann et al., 2006; Ling et al., 2013) .”
BackgroundInfluentialRaman, R., Allen, S. P., Goodall, G., Kramer, S., Ponger, L., Heath, P. R., Milo, M., Hollinger, H. C., Walsh, T., Highley, J. R., et al. (2014) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12147 · Cited by 254
“following on from the earlier literature identifying angiogenin (ANG) [58] and senataxin (SETX) [59] as RNA-related proteins which are mutated in ALS, there is now substantial evidence of dysregulated RNA processing contributing to the pathogenesis of both genetic and sporadic ALS [60, 61].”
BackgroundStoica, R., Paillusson, S., Gómez‐Suaga, P., Mitchell, J. C., Lau, D. H. W., Gray, E. H., Sancho, R. M., Vizcay‐Barrena, G., Vos, K. J. D., Shaw, C. E., et al. (2016) · EMBO Reports · doi:10.15252/embr.201541726 · Cited by 269
“ALS is the most common form of motor neuron disease, and FTD is the second most common form of presenile dementia after Alzheimer’s disease [7].”
An emerging role for misfolded wild-type SOD1 in sporadic ALS pathogenesis
Rotunno, M. S., & Bosco, D. A. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00253 · Cited by 256
“Despite decades of research on FALS-SOD1 in vitro and in vivo, the exact mechanism of SOD1 in ALS pathogenesis remains unknown (Pasinelli and Brown, 2006; Ling et al., 2013).”
BackgroundScekic‐Zahirovic, J., Sendscheid, O., Oussini, H. E., Jambeau, M., Sun, Y., Mersmann, S., Wagner, M., Dieterle, S., Sinniger, J., Dirrig‐Grosch, S., et al. (2016) · The EMBO Journal · doi:10.15252/embj.201592559 · Cited by 262
“…hundreds of genes (Polymenidou et al , 2011; Tollervey et al , 2011; Ishigaki et al , 2012; Lagier-Tourenne et al , 2012; Rogelj et al , 2012; Ling et al , 2015), and both proteins are critically involved in the processing of long pre-mRNAs (Polymenidou et al , 2011; Lagier-Tourenne et al ,…”
BackgroundMechanism of STMN2 cryptic splice-polyadenylation and its correction for TDP-43 proteinopathies
Baughn, M. W., Melamed, Z., López‐Erauskin, J., Beccari, M. S., Ling, K., Zuberi, A. R., Presa, M. F., Gonzalo-Gil, E., Maimon, R., Vazquez‐Sanchez, S., et al. (2023) · Science · doi:10.1126/science.abq5622 · Cited by 252
Self-citationRoot, J. T., Merino, P., Nuckols, A., Johnson, M. A., & Kukar, T. L. (2021) · Neurobiology of Disease · doi:10.1016/j.nbd.2021.105360 · Cited by 243
A C9ORF72/SMCR8-containing complex regulates ULK1 and plays a dual role in autophagy
Yang, M., Liang, C., Swaminathan, K., Herrlinger, S., Lai, F., Shiekhattar, R., & Chen, J.-F. (2016) · Science Advances · doi:10.1126/sciadv.1601167 · Cited by 238
Filadi, R., Theurey, P., & Pizzo, P. (2017) · Cell Calcium · doi:10.1016/j.ceca.2017.01.003 · Cited by 247
SOD1, more than just an antioxidant
Eleuthério, E. C. A., Magalhães, R. S. S., Brasil, A. D. A., Neto, J. R. M., & Paranhos, L. H. (2020) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2020.108701 · Cited by 252
Loss of Nuclear TDP-43 Is Associated with Decondensation of LINE Retrotransposons
Liu, E. Y., Russ, J., Cali, C. P., Phan, J. M., Amlie-Wolf, A., & Lee, E. B. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.04.003 · Cited by 231
“, 2017), and genetic mutations have been linked to both diseases (Ling et al., 2013).”
BackgroundDeng, Z., Lim, J., Wang, Q., Purtell, K., Wu, S., Palomo, G. M., Tan, H., Manfredi, G., Zhao, Y., Peng, J., et al. (2019) · Autophagy · doi:10.1080/15548627.2019.1644076 · Cited by 237
Molecular Mechanisms of mtDNA-Mediated Inflammation
Gaetano, A. D., Solodka, K., Zanini, G., Selleri, V., Mattioli, A. V., Nasi, M., & Pinti, M. (2021) · Cells · doi:10.3390/cells10112898 · Cited by 241
Kramer, N. J., Haney, M. S., Morgens, D. W., Jovičić, A., Couthouis, J., Li, A., Ousey, J., Ma, R., Bieri, G., Tsui, C. K., et al. (2018) · Nature Genetics · doi:10.1038/s41588-018-0070-7 · Cited by 226
“Aggregates of the RNA-binding protein TDP-43 accumulate in neurons of nearly all ALS cases and almost half of FTD cases 3 and mutations in several genes can cause ALS, FTD, or even both (ALS/FTD) 4 .”
Hanan, M., Soreq, H., & Kadener, S. (2017) · RNA Biology · doi:10.1080/15476286.2016.1255398 · Cited by 229
NMR spectroscopy captures the essential role of dynamics in regulating biomolecular function
Alderson, T. R., & Kay, L. E. (2021) · Cell · doi:10.1016/j.cell.2020.12.034 · Cited by 233
Amyotrophic lateral sclerosis: mechanisms and therapeutics in the epigenomic era
Paez-Colasante, X., Figueroa‐Romero, C., Sakowski, S. A., Goutman, S. A., & Feldman, E. L. (2015) · Nature Reviews Neurology · doi:10.1038/nrneurol.2015.57 · Cited by 227
Advances in treating amyotrophic lateral sclerosis: insights from pathophysiological studies
Vucic, S., Rothstein, J. D., & Kiernan, M. C. (2014) · Trends in Neurosciences · doi:10.1016/j.tins.2014.05.006 · Cited by 233
RNA-binding proteins in neurodegeneration: mechanisms in aggregatePreprint
Conlon, E. G., & Manley, J. L. (2017) · Genes & Development · doi:10.1101/gad.304055.117 · Cited by 229
“We also note that a significant class of ALS without TDP-43 pathology is caused by mutations in superoxide dismutase 1 (SOD1), and the mechanism of disease is not believed to involveRBPs or their aggregation (Ling et al. 2013).”
BackgroundInfluentialG‐quadruplexes: Emerging roles in neurodegenerative diseases and the non‐coding transcriptome
Simone, R., Fratta, P., Neidle, S., Parkinson, G. N., & Isaacs, A. M. (2015) · FEBS Letters · doi:10.1016/j.febslet.2015.05.003 · Cited by 217
“Accumulating evidence suggests that these two diseases form a continuum, with a spectrum of phenotypic variants of the same pathological process, which involves altered homeostasis of key master regulators like the DNA–RNA binding proteins TDP-43 and FUS [74,75].”
BackgroundGao, F., Almeida, S., & Lopez‐Gonzalez, R. (2017) · The EMBO Journal · doi:10.15252/embj.201797568 · Cited by 227
“Both TDP-43 and FUS are involved in multiple aspects of RNA metabolism, and the frequent presence of either TDP-43 or FUS pathology in both ALS and FTD strongly suggests a common pathogenic mechanism involving defective RNA metabolism (Ling et al , 2013).”
March, Z. M., King, O. D., & Shorter, J. (2016) · Brain Research · doi:10.1016/j.brainres.2016.02.037 · Cited by 223
“…can promote deleterious TDP-43 misfolding and enhance proteotoxicity in diverse model systems (Barmada et al., 2010; Guo et al., 2011; Johnson et al., 2009; Kabashi et al., 2010; Li et al., 2010; Lim et al., 2016; Ling et al., 2013; Ritson et al., 2010; Sreedharan et al., 2008; Zhang et al., 2009).”
Loughlin, F. E., Lukavsky, P. J., Kazeeva, T., Reber, S., Hock, E., Colombo, M., von Schroetter, C., Pauli, P., Cléry, A., Mühlemann, O., et al. (2018) · Molecular Cell · doi:10.1016/j.molcel.2018.11.012 · Cited by 207
“The two neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and fronto-temporal lobar degeneration (FTLD) show neuropathological protein aggregates containing FUS, and it is hypothesized that mis-regulation of RNA processing could play a major role in these diseases (Ling et al., 2013; Ramaswami et al., 201…”
BackgroundSelf-citationEmde, A., Eitan, C., Liou, L., Libby, R. T., Rivkin, N., Magen, I., Reichenstein, I., Oppenheim, H., Eilam, R., Silvestroni, A., et al. (2015) · The EMBO Journal · doi:10.15252/embj.201490493 · Cited by 217
“…, 2010; Liu-Yesucevitz et al , 2010; Dewey et al , 2011; McDonald et al , 2011; Meyerowitz et al , 2011; Aulas et al , 2012; Baron et al , 2013; Daigle et al , 2013; Kim et al , 2013; Vance et al , 2013; reviewed in Dewey et al , 2012; Emde & Hornstein, 2014; Li et al , 2013b; Ling et al , 2013).”
ALS-Associated FUS Mutations Result in Compromised FUS Alternative Splicing and Autoregulation
Zhou, Y., Liu, S., Liu, G., Öztürk, A., & Hicks, G. G. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003895 · Cited by 223
“Mice and rats expressing TDP-43 without the autoregulatory sequence developed more severe neurodegeneration than those expressing autoregulated wildtype or ALS-linked TDP-43 mutants, strongly suggesting deficient TDP-43 autoregulation contributes to neurodegeneration [57].”
BackgroundThe multi-dimensional roles of astrocytes in ALS
Yamanaka, K., & Komine, O. (2017) · Neuroscience Research · doi:10.1016/j.neures.2017.09.011 · Cited by 220
The Role of Skeletal Muscle in Amyotrophic Lateral Sclerosis
Loeffler, J., Picchiarelli, G., Dupuis, L., & de Aguilar, J. G. (2016) · Brain Pathology · doi:10.1111/bpa.12350 · Cited by 208
CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia
Williams, K. L., Topp, S. D., Yang, S., Smith, B. N., Fifita, J. A., Warraich, S. T., Zhang, K. Y., Farrawell, N. E., Vance, C. A., Hu, X., et al. (2016) · Nature Communications · doi:10.1038/ncomms11253 · Cited by 220
TDP-43 aggregation induced by oxidative stress causes global mitochondrial imbalance in ALS
Zuo, X., Zhou, J., Li, Y., Wu, K., Chen, Z., Luo, Z., Zhang, X., Liang, Y., Esteban, M. A., Zhou, Y., et al. (2021) · Nature Structural & Molecular Biology · doi:10.1038/s41594-020-00537-7 · Cited by 214
Cheng, W., Wang, S., Mestre, A. A., Fu, C., Makarem, A. O., Xian, F., Hayes, L. R., Lopez-Gonzalez, R., Drenner, K., Jiang, J., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-02495-z · Cited by 199
Self-citationRetrotransposon activation contributes to neurodegeneration in a Drosophila TDP-43 model of ALS
Krug, L., Chatterjee, N., Borges-Monroy, R., Hearn, S., Liao, W.-W., Morrill, K., Prazak, L., Rozhkov, N., Theodorou, D., Hammell, M., et al. (2017) · PLOS Genetics · doi:10.1371/journal.pgen.1006635 · Cited by 201
“cytoplasmic aggregates are thought to contribute to disease progression (25-27, 37, 38, 64, 66).”
BackgroundInfluentialDisease‐linked TDP‐43 hyperphosphorylation suppresses TDP‐43 condensation and aggregation
Gruijs da Silva, L. A., Simonetti, F., Hutten, S., Riemenschneider, H., Sternburg, E. L., Pietrek, L. M., Gebel, J., Dötsch, V., Edbauer, D., Hummer, G., et al. (2022) · The EMBO Journal · doi:10.15252/embj.2021108443 · Cited by 192
“…and both loss-of-function mechanisms, e.g., misregulation of nuclear RNA targets, and gain-of-function mechanisms, e.g., aberrant interactions of the TDP-43 aggregates, are believed to contribute to neuronal dysfunction and eventually neurodegeneration (Ling et al , 2013; Tziortzouda et al , 2021).”
Mitochondria Associated Membranes (MAMs): Architecture and physiopathological role
Barazzuol, L., Giamogante, F., & Calí, T. (2021) · Cell Calcium · doi:10.1016/j.ceca.2020.102343 · Cited by 213
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
