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Kaitlin Weskamp, … , Jemeen Sreedharan, Sami J. Barmada
Published November 12, 2019
Citation Information: J Clin Invest. 2020;130(3):1139-1155. https://doi.org/10.1172/JCI130988.
Citation Information: J Clin Invest. 2020;130(3):1139-1155. https://doi.org/10.1172/JCI130988.
Abstract
Cortical hyperexcitability and mislocalization of the RNA-binding protein TDP43 are highly conserved features in amyotrophic lateral sclerosis (ALS). Nevertheless, the relationship between these phenomena remains poorly defined. Here, we showed that hyperexcitability recapitulates TDP43 pathology by upregulating shortened TDP43 (sTDP43) splice isoforms. These truncated isoforms accumulated in the cytoplasm and formed insoluble inclusions that sequestered full-length TDP43 via preserved N-terminal interactions. Consistent with these findings, sTDP43 overexpression was toxic to mammalian neurons, suggesting neurodegeneration arising from complementary gain- and loss-of-function mechanisms. In humans and mice, sTDP43 transcripts were enriched in vulnerable motor neurons, and we observed a striking accumulation of sTDP43 within neurons and glia of ALS patients. Collectively, these studies uncover a pathogenic role for alternative TDP43 isoforms in ALS, and implicate sTDP43 as a key contributor to the susceptibility of motor neurons in this disorder.
Authors
Kaitlin Weskamp, Elizabeth M. Tank, Roberto Miguez, Jonathon P. McBride, Nicolás B. Gómez, Matthew White, Ziqiang Lin, Carmen Moreno Gonzalez, Andrea Serio, Jemeen Sreedharan, Sami J. Barmada
Citation information
Citations to this article (73)
| Title and authors | Publication | Year |
|---|---|---|
|
TDP-43 pathology is sufficient to drive axon initial segment plasticity and hyperexcitability of spinal motoneurones in vivo in the TDP43-ΔNLS model of Amyotrophic Lateral Sclerosis
Djukic S, Zhao Z, Jørgensen LM, Bak AN, Jensen DB, Meehan CF |
Acta Neuropathologica Communications | 2025 |
|
TDP43 autoregulation gives rise to dominant negative isoforms that are tightly controlled by transcriptional and post-translational mechanisms
Dykstra MM, Weskamp K, Gómez NB, Waksmacki J, Tank E, Glineburg MR, Snyder A, Pinarbasi E, Bekier M, Li X, Miller MR, Bai J, Shahzad S, Nedumaran N, Wieland C, Stewart C, Willey S, Grotewold N, McBride J, Moran JJ, Suryakumar AV, Lucas M, Tessier PM, Ward M, Todd PK, Barmada SJ |
Cell reports | 2025 |
|
Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS
Bekier ME II, Pinarbasi E, Mesojedec JJ, Ghaffari L, de Majo M, Ullian E, Koontz M, Coleman S, Li X, Tank EM, Waksmacki J, Barmada S |
bioRxiv | 2025 |
|
Neuronal Activity-Dependent Gene Dysregulation in C9orf72 i3Neuronal Models of ALS/FTD Pathogenesis
Ghaffari LT, Welebob E, Boehringer A, Cyliax K, Pasinelli P, Trotti D, Haeusler AR |
bioRxiv | 2025 |
|
The Effect of Repetitive Transcranial Magnetic Stimulation of the Dorsolateral Prefrontal Cortex on the Amyotrophic Lateral Sclerosis Patients With Cognitive Impairment: A Double‐Blinded, Randomized, and Sham Control Trial
Zheng W, Zhang X, Chen J, Luan X, Wang J, Zhang L, Liu K, Zhao Y, Xu Z |
CNS Neuroscience & Therapeutics | 2025 |
|
An autism spectrum disorder mutation in Topoisomerase 3β causes accumulation of covalent mRNA intermediates by disrupting metal binding within the zinc finger domain
Warrick JE, Attili D, van Eeuwen T, Hoffmann-Weitsman SE, Forsyth NC, Barmada SJ, Kearse MG |
bioRxiv | 2025 |
|
RNA-binding proteins in ALS and FTD: from pathogenic mechanisms to therapeutic insights
Rummens J, Da Cruz S |
Molecular Neurodegeneration | 2025 |
|
Nuclear-import receptors as gatekeepers of pathological phase transitions in ALS/FTD
Khalil B, Linsenmeier M, Smith CL, Shorter J, Rossoll W |
Molecular Neurodegeneration | 2024 |
|
Reevaluating Golgi fragmentation and its implications in wound repair.
Wijaya CS, Xu S |
2024 | |
|
Homozygous ALS-linked mutations in TARDBP/TDP-43 lead to hypoactivity and synaptic abnormalities in human iPSC-derived motor neurons.
Lépine S, Nauleau-Javaudin A, Deneault E, Chen CX, Abdian N, Franco-Flores AK, Haghi G, Castellanos-Montiel MJ, Maussion G, Chaineau M, Durcan TM |
iScience | 2024 |
|
Betz cells of the primary motor cortex
Nolan M, Scott C, Hof PR, Ansorge O |
The Journal of Comparative Neurology | 2024 |
|
Biochemical, Biomarker, and Behavioral Characterization of the Grn(R493X) Mouse Model of Frontotemporal Dementia.
Smith DM, Aggarwal G, Niehoff ML, Jones SA, Banerjee S, Farr SA, Nguyen AD |
Molecular Neurobiology | 2024 |
|
Neuronal Circuit Dysfunction in Amyotrophic Lateral Sclerosis.
Salzinger A, Ramesh V, Das Sharma S, Chandran S, Thangaraj Selvaraj B |
Cells | 2024 |
|
Splicing regulation through biomolecular condensates and membraneless organelles.
Giudice J, Jiang H |
Nature reviews. Molecular cell biology | 2024 |
|
Aberrant CHCHD2-associated mitochondriopathy in Kii ALS/PDC astrocytes.
Leventoux N, Morimoto S, Ishikawa M, Nakamura S, Ozawa F, Kobayashi R, Watanabe H, Supakul S, Okamoto S, Zhou Z, Kobayashi H, Kato C, Hirokawa Y, Aiba I, Takahashi S, Shibata S, Takao M, Yoshida M, Endo F, Yamanaka K, Kokubo Y, Okano H |
Acta Neuropathologica | 2024 |
|
Nanoplastics and Neurodegeneration in ALS
Eisen A, Pioro EP, Goutman SA, Kiernan MC |
Brain Sciences | 2024 |
|
Ribosomal quality control factors inhibit repeat-associated non-AUG translation from GC-rich repeats
Tseng YJ, Krans A, Malik I, Deng X, Yildirim E, Ovunc S, Tank EM, Jansen-West K, Kaufhold R, Gomez NB, Sher R, Petrucelli L, Barmada SJ, Todd PK |
Nucleic Acids Research | 2024 |
|
TDP43 autoregulation gives rise to shortened isoforms that are tightly controlled by both transcriptional and post-translational mechanisms
Dykstra MM, Weskamp K, Gómez NB, Waksmacki J, Tank E, Glineburg MR, Snyder A, Pinarbasi E, Bekier M, Li X, Bai J, Shahzad S, Nedumaran J, Wieland C, Stewart C, Willey S, Grotewold N, McBride J, Moran JJ, Suryakumar AV, Lucas M, Tessier P, Ward M, Todd P, Barmada SJ |
2024 | |
|
Multivalent GU-rich oligonucleotides sequester TDP-43 in the nucleus by inducing high molecular weight RNP complexes
Zhang X, Das T, Chao TF, Trinh V, Carmen-Orozco RP, Ling JP, Kalab P, Hayes LR |
iScience | 2024 |
|
Molecular Visualization of Neuronal TDP43 Pathology In Situ
Erwin AL, Chang ML, Fernandez MG, Attili D, Russ JE, Sutanto R, Pinarbasi ES, Bekier M, Brant TS, Hahn T, Dykstra M, Thomas D, Li X, Baldridge RD, Tank EM, Barmada SJ, Mosalaganti S |
bioRxiv | 2024 |
|
Location and function of TDP-43 in platelets, alterations in neurodegenerative diseases and arising considerations for current plasma biobank protocols.
Luthi-Carter R, Cappelli S, Le Roux-Bourdieu M, Tentillier N, Quinn JP, Petrozziello T, Gopalakrishnan L, Sethi P, Choudhary H, Bartolini G, Gebara E, Stuani C, Font L, An J, Ortega V, Sage J, Kosa E, Trombetta BA, Simeone R, Seredenina T, Afroz T, Berry JD, Arnold SE, Carlyle BC, Adolfsson O, Sadri-Vakili G, Buratti E, Bowser R, Agbas A |
Scientific reports | 2024 |
|
β-synuclein regulates the phase transitions and amyloid conversion of α-synuclein.
Li X, Yu L, Liu X, Shi T, Zhang Y, Xiao Y, Wang C, Song L, Li N, Liu X, Chen Y, Petersen RB, Cheng X, Xue W, Yu YV, Xu L, Zheng L, Chen H, Huang K |
Nature communications | 2024 |
|
Regulation of TAR DNA binding protein 43 (TDP-43) homeostasis by cytosolic DNA accumulation
Yang C, Leifer C, Lammerding J, Hu F |
The Journal of Biological Chemistry | 2024 |
|
Reduction of Nemo-like kinase increases lysosome biogenesis and ameliorates TDP-43-related neurodegeneration
Leon Tejwani, Hiroshi Kokubu, Paul J Lee, Yangfei Xiang, Kimberly Luttik, Armand Soriano, Jennifer Yoon, Junhyun Park, Hannah Ro, Hyoungseok Ju, Clara Liao, Sofia Tieze, Frank Rigo, Paymaan Jafar-Nejad, Janghoo Lim |
Journal of Clinical Investigation | 2023 |
|
RNA methylation influences TDP43 binding and disease pathogenesis in models of amyotrophic lateral sclerosis and frontotemporal dementia
McMillan M, Gomez N, Hsieh C, Bekier M, Li X, Miguez R, Tank EM, Barmada SJ |
Molecular Cell | 2023 |
|
ILF3 prion-like domain regulates gene expression and fear memory under chronic stress
Yamashita A, Shichino Y, Fujii K, Koshidaka Y, Adachi M, Sasagawa E, Mito M, Nakagawa S, Iwasaki S, Takao K, Shiina N |
iScience | 2023 |
|
Neuronal activity regulates Matrin 3 abundance and function in a calcium-dependent manner through calpain-mediated cleavage and calmodulin binding.
Malik AM, Wu JJ, Gillies CA, Doctrove QA, Li X, Huang H, Tank EHM, Shakkottai VG, Barmada S |
Proceedings of the National Academy of Sciences | 2023 |
|
Astrocytic TDP-43 dysregulation impairs memory by modulating antiviral pathways and interferon-inducible chemokines
Licht-Murava A, Meadows SM, Palaguachi F, Song SC, Jackvony S, Bram Y, Zhou C, Schwartz RE, Froemke RC, Orr AL, Orr AG |
Science Advances | 2023 |
|
Mitigating a TDP-43 proteinopathy using RNA-targeting CRISPR effector proteins
Zeballos C. MA, Moore HJ, Powell JE, Smith TJ, Zhang S, Gaj T |
2023 | |
|
Differential response of C9orf72 transcripts following neuronal depolarization
Ghaffari LT, Trotti D, Haeusler AR |
iScience | 2023 |
|
Biomolecular condensates – extant relics or evolving microcompartments?
Rangachari V |
Communications biology | 2023 |
|
Ribosomal quality control factors inhibit repeat-associated non-AUG translation from GC-rich repeats
Tseng YJ, Malik I, Deng X, Krans A, Jansen-West K, Tank EM, Gomez NB, Sher R, Petrucelli L, Barmada SJ, Todd PK |
2023 | |
|
Biochemical, biomarker, and behavioral characterization of the GrnR493X mouse model of frontotemporal dementia
Smith DM, Aggarwal G, Niehoff ML, Jones SA, Banerjee S, Farr SA, Nguyen AD |
2023 | |
|
Unraveling the impact of disrupted nucleocytoplasmic transport systems in C9orf72-associated ALS
McGoldrick P, Robertson J |
Frontiers in cellular neuroscience | 2023 |
|
TDP-43 Epigenetic Facets and Their Neurodegenerative Implications
Gimenez J, Spalloni A, Cappelli S, Ciaiola F, Orlando V, Buratti E, Longone P |
International journal of molecular sciences | 2023 |
|
Mitigating a TDP-43 proteinopathy by targeting ataxin-2 using RNA-targeting CRISPR effector proteins
Zeballos C. MA, Moore HJ, Smith TJ, Powell JE, Ahsan NS, Zhang S, Gaj T |
Nature Communications | 2023 |
|
Astrocytes as Drivers and Disruptors of Behavior: New Advances in Basic Mechanisms and Therapeutic Targeting
Barnett D, Bohmbach K, Grelot V, Charlet A, Dallérac G, Ju YH, Nagai J, Orr AG |
Journal of Neuroscience | 2023 |
|
TDP-43 Cytoplasmic Translocation in the Skin Fibroblasts of ALS Patients
M Rubio, M Herrando-Grabulosa, R Velasco, I Blasco, M Povedano, X Navarro |
Cells | 2022 |
|
Expanding the TDP-43 Proteinopathy Pathway From Neurons to Muscle: Physiological and Pathophysiological Functions
L Versluys, P Pereira, N Schuermans, B Paepe, J Bleecker, E Bogaert, B Dermaut |
Frontiers in neuroscience | 2022 |
|
Tofacitinib Suppresses Natural Killer Cells In Vitro and In Vivo: Implications for Amyotrophic Lateral Sclerosis
C Figueroa-Romero, A Monteagudo, B Murdock, J Famie, I Webber-Davis, C Piecuch, S Teener, C Pacut, S Goutman, E Feldman |
Frontiers in immunology | 2022 |
|
Dysregulation of Translation in TDP-43 Proteinopathies: Deficits in the RNA Supply Chain and Local Protein Production
R Bjork, N Mortimore, S Loganathan, D Zarnescu |
Frontiers in neuroscience | 2022 |
|
TDP-43 Oligomerization and Phase Separation Properties Are Necessary for Autoregulation
L Koehler, Z Grese, A Bastos, L Mamede, T Heyduk, Y Ayala |
Frontiers in neuroscience | 2022 |
|
DNA Double-Strand Breaks as Pathogenic Lesions in Neurological Disorders
V Provasek, J Mitra, V Malojirao, M Hegde |
International journal of molecular sciences | 2022 |
|
TDP-35, a truncated fragment of TDP-43, induces dose-dependent toxicity and apoptosis in flies
D Chhangani, D Rincon-Limas |
NEURAL REGEN RES | 2022 |
|
Myotubularin-related phosphatase 5 is a critical determinant of autophagy in neurons
Chua JP, Bedi K, Paulsen MT, Ljungman M, Tank EM, Kim ES, McBride JP, Colón-Mercado JM, Ward ME, Weisman LS, Barmada SJ |
Current biology : CB | 2022 |
|
RNA-binding proteins direct myogenic cell fate decisions
Wheeler JR, Whitney ON, Vogler TO, Nguyen ED, Pawlikowski B, Lester E, Cutler A, Elston T, Dalla Betta N, Parker KR, Yost KE, Vogel H, Rando TA, Chang HY, Johnson AM, Parker R, Olwin BB |
eLife | 2022 |
|
Aging-Dependent Altered Transcriptional Programs Underlie Activity Impairments in Human C9orf72-Mutant Motor Neurons
Sommer D, Rajkumar S, Seidel M, Aly A, Ludolph A, Ho R, Boeckers TM, Catanese A |
Frontiers in molecular neuroscience | 2022 |
|
A C-Terminally Truncated TDP-43 Splice Isoform Exhibits Neuronal Specific Cytoplasmic Aggregation and Contributes to TDP-43 Pathology in ALS
Shenouda M, Xiao S, MacNair L, Lau A, Robertson J |
Frontiers in neuroscience | 2022 |
|
Nuclear RNA binding regulates TDP-43 nuclear localization and passive nuclear export.
Duan L, Zaepfel BL, Aksenova V, Dasso M, Rothstein JD, Kalab P, Hayes LR |
Cell Reports | 2022 |
|
Nuclear import receptors are recruited by FG-nucleoporins to rescue hallmarks of TDP-43 proteinopathy.
Khalil B, Chhangani D, Wren MC, Smith CL, Lee JH, Li X, Puttinger C, Tsai CW, Fortin G, Morderer D, Gao J, Liu F, Lim CK, Chen J, Chou CC, Croft CL, Gleixner AM, Donnelly CJ, Golde TE, Petrucelli L, Oskarsson B, Dickson DW, Zhang K, Shorter J, Yoshimura SH, Barmada SJ, Rincon-Limas DE, Rossoll W |
Molecular Neurodegeneration | 2022 |
|
Development of a specific live-cell assay for native autophagic flux
N Safren, EM Tank, AM Malik, JP Chua, N Santoro, SJ Barmada |
The Journal of biological chemistry | 2021 |
|
Triad of TDP43 control in neurodegeneration: autoregulation, localization and aggregation
P Tziortzouda, LV Bosch, F Hirth |
Nature Reviews Neuroscience | 2021 |
|
Characterization of the human TARDBP gene promoter
M Baralle, M Romano |
Scientific Reports | 2021 |
|
Cytoplasmic Human TDP-43 Mislocalization Induces Widespread Dendritic Spine Loss in Mouse Upper Motor Neurons
MS Dyer, A Woodhouse, CA Blizzard |
Brain Sciences | 2021 |
|
Extracellular Vesicles in Serum and Central Nervous System Tissues Contain microRNA Signatures in Sporadic Amyotrophic Lateral Sclerosis
T Lo, C Figueroa-Romero, J Hur, C Pacut, E Stoll, C Spring, R Lewis, A Nair, SA Goutman, SA Sakowski, S Nagrath, EL Feldman |
Frontiers in molecular neuroscience | 2021 |
|
Human sensorimotor organoids derived from healthy and amyotrophic lateral sclerosis stem cells form neuromuscular junctions
JD Pereira, DM DuBreuil, AC Devlin, A Held, Y Sapir, E Berezovski, J Hawrot, K Dorfman, V Chander, BJ Wainger |
Nature Communications | 2021 |
|
Effect of Ezogabine on Cortical and Spinal Motor Neuron Excitability in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial
BJ Wainger, EA Macklin, S Vucic, CE McIlduff, S Paganoni, NJ Maragakis, R Bedlack, NA Goyal, SB Rutkove, DJ Lange, MH Rivner, SA Goutman, SS Ladha, EA Mauricio, RH Baloh, Z Simmons, L Pothier, SB Kassis, T La, M Hall, A Evora, D Klements, A Hurtado, JD Pereira, J Koh, PA Celnik, V Chaudhry, K Gable, VC Juel, N Phielipp, A Marei, P Rosenquist, S Meehan, B Oskarsson, RA Lewis, D Kaur, E Kiskinis, CJ Woolf, K Eggan, MD Weiss, JD Berry, WS David, P Davila-Perez, JA Camprodon, A Pascual-Leone, MC Kiernan, JM Shefner, N Atassi, ME Cudkowicz |
JAMA NEUROL | 2021 |
|
Emerging Mechanisms Underpinning Neurophysiological Impairments in C9ORF72 Repeat Expansion-Mediated Amyotrophic Lateral Sclerosis/Frontotemporal Dementia
IS Pasniceanu, MS Atwal, CD Souza, L Ferraiuolo, MR Livesey |
Frontiers in cellular neuroscience | 2021 |
|
Multi-phaseted problems of TDP-43 in selective neuronal vulnerability in ALS
K Asakawa, H Handa, K Kawakami |
Cellular and Molecular Life Sciences | 2021 |
|
Molecular, functional, and pathological aspects of TDP-43 fragmentation
D Chhangani, A Martín-Peña, DE Rincon-Limas |
iScience | 2021 |
|
RNA Is a Double-Edged Sword in ALS Pathogenesis
BL Zaepfel, JD Rothstein |
Frontiers in cellular neuroscience | 2021 |
|
Brain Stimulation as a Therapeutic Tool in Amyotrophic Lateral Sclerosis: Current Status and Interaction With Mechanisms of Altered Cortical Excitability
F Ranieri, S Mariotto, R Dubbioso, VD Lazzaro |
Frontiers in neurology | 2021 |
|
Dangerous Stops: Nonsense Mutations Can Dramatically Increase Frequency of Prion Conversion
AA Dergalev, VN Urakov, MO Agaphonov, AI Alexandrov, VV Kushnirov |
International journal of molecular sciences | 2021 |
|
Human amyotrophic lateral sclerosis excitability phenotype screen: Target discovery and validation
X Huang, KC Roet, L Zhang, A Brault, AP Berg, AB Jefferson, J Klug-McLeod, KL Leach, F Vincent, H Yang, AJ Coyle, LH Jones, D Frost, O Wiskow, K Chen, R Maeda, A Grantham, MK Dornon, JR Klim, MT Siekmann, D Zhao, S Lee, K Eggan, CJ Woolf |
Cell Reports | 2021 |
|
It’s not just a phase: function and characteristics of RNA-binding proteins in phase separation
HJ Wiedner, J Giudice |
Nature Structural & Molecular Biology | 2021 |
|
Enhanced detection of expanded repeat mRNA foci with hybridization chain reaction
MR Glineburg, Y Zhang, A Krans, EM Tank, SJ Barmada, PK Todd |
Acta Neuropathologica Communications | 2021 |
|
TDP43 ribonucleoprotein granules: physiologic function to pathologic aggregates
G Corbet, J Wheeler, R Parker, K Weskamp |
RNA biology | 2021 |
|
Cerebral sterile inflammation in neurodegenerative diseases
K Otani, T Shichita |
Inflammation and Regeneration | 2020 |
|
The role of TDP-43 mislocalization in amyotrophic lateral sclerosis
TR Suk, MW Rousseaux |
Molecular Neurodegeneration | 2020 |
|
Omics Approach to Axonal Dysfunction of Motor Neurons in Amyotrophic Lateral Sclerosis (ALS)
N Suzuki, T Akiyama, H Warita, M Aoki |
Frontiers in neuroscience | 2020 |
|
Cytoplasmic TDP43 Binds microRNAs: New Disease Targets in Amyotrophic Lateral Sclerosis
X Paez-Colasante, C Figueroa-Romero, AE Rumora, J Hur, FE Mendelson, JM Hayes, C Backus, GF Taubman, L Heinicke, NG Walter, SJ Barmada, SA Sakowski, EL Feldman |
Frontiers in cellular neuroscience | 2020 |
|
Stress Granule Assembly Can Facilitate but Is Not Required for TDP-43 Cytoplasmic Aggregation
N Fernandes, L Nero, SM Lyons, P Ivanov, TM Mittelmeier, TA Bolger, JR Buchan |
Biomolecules | 2020 |
|
Cortical Circuit Dysfunction as a Potential Driver of Amyotrophic Lateral Sclerosis
A Brunet, G Stuart-Lopez, T Burg, J Scekic-Zahirovic, C Rouaux |
Frontiers in neuroscience | 2020 |
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