Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) overlap considerably in genetic origin and pathology. Multiple C. elegans models of ALS/FTD have been developed, but the integrity of glutamatergic neurons in these models has not been thoroughly evaluated. Here, we report degeneration of glutamatergic phasmid neurons in animals expressing either wild-type or disease variant V337M human tau, but not in animals expressing disease variants of human TDP-43. Defects caused by ectopic expression of tau were suppressed by loss of the known modifier, spop-1, suggesting that SPOP-1-dependent pathways are also involved in glutamatergic neuron degeneration.
","acknowledgements":"Strains were provided by the CGC (funded by NIH Office of Research Infrastructure Programs, P40 OD010440), National BioResources Project of Japan. We also thank Dr. Brian Kraemer (Univ. of Washington) for providing previously published strains.
","authors":[{"affiliations":["Brown University, Providence, RI, United States","Carney Institute for Brain Science, Providence, RI, United States"],"departments":["Neuroscience",""],"credit":["conceptualization","formalAnalysis","investigation","methodology","validation","visualization","writing_originalDraft"],"email":"lexi-amber_hassell@brown.edu","firstName":"Lexi-Amber","lastName":"Hassell","submittingAuthor":true,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":"0000-0002-9921-0088"},{"affiliations":["Brown University, Providence, RI, United States"],"departments":["Neuroscience"],"credit":["investigation","writing_reviewEditing"],"email":"mika_gallati@alumni.brown.edu","firstName":"Mika","lastName":"Gallati","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":"0000-0001-8980-5814"},{"affiliations":["Brown University, Providence, RI, United States"],"departments":["Neuroscience"],"credit":["investigation","writing_reviewEditing","visualization"],"email":"monica_thoma@brown.edu","firstName":"Monica","lastName":"Thoma","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["Brown University, Providence, RI, United States"],"departments":["Neuroscience"],"credit":["investigation","writing_originalDraft"],"email":"selamawit_asfaw@alumni.brown.edu","firstName":"Selamawit","lastName":"Asfaw","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["Brown University, Providence, RI, United States","Carney Institute for Brain Science, Providence, RI, United States"],"departments":["Neuroscience",""],"credit":["conceptualization","fundingAcquisition","methodology","project","supervision","writing_reviewEditing"],"email":"anne_hart@brown.edu","firstName":"Anne Church","lastName":"Hart","submittingAuthor":false,"correspondingAuthor":true,"equalContribution":false,"WBId":null,"orcid":"0000-00017239-4350"}],"awards":[],"conflictsOfInterest":"The authors declare that there are no conflicts of interest present.
","dataTable":{"url":null},"extendedData":[],"funding":"Supported in part by NIH R21NS116254 (ACH). MT was supported by the Undergraduate Teaching Research Award. LAH was supported by the Predoctoral Training Program in Biological Data Science (NIH T32 GM149433) and the Interdisciplinary Predoctoral Neuroscience Training Program in the Neuroscience Graduate Program (NIH T32 MH020068).
","image":{"url":"https://portal.micropublication.org/uploads/050a5fea746698fbe29038554c2e8af7.png"},"imageCaption":"A) Four phasmid neurons in the tail dye-fill when intact. Degenerated neurons fail to dye-fill. B) This study uses animals with transgenes expressing hTau WT, hTau V337M, hTDP-43 A315T, and hTDP-43 M337V under pan-neuronal promoters. C) All animals expressing hTau have dye-filling defects suppressed by spop-1 loss of function (Δ = deletion allele, spop-1(dr172); R414* = early stop codon, spop-1(bk4000)). Statistical values were calculated by one-way ANOVA multiple comparison tests. Statistical comparisons between N2 and Tau(low), Tau(high), or Tau(V337M) were made using only animals scored in the same trials. These were combined to make one summary panel shown here. Not shown: spop-1 loss rescues Tau(low) and Tau(V337M) back to WT, but not Tau(high) (p<0.01). D) Animals expressing TDP-43(A315T) do not have dye-filling defects, whereas animals expressing TDP-43(M337V) have minor, but significant dye-filling defects compared to N2 animals trialed on the same days. Statistical values were calculated by unpaired t-tests. ns = p>0.05, * = p<0.05, ** = p<0.01, *** = p<0.001, **** =p<0.0001
","imageTitle":"C. elegans models of ALS/FTD have varying degrees of dye-filling defects
","methods":"Strains were maintained at 20˚C on NGM plates and OP50 E. coli.
Dye-filling
L4 animals were picked 18 hours before dye-filling to seeded NGM plates. After 18 hours, Day 1 adults were suspended on a shaker in 500 uL of 0.012 mg/mL DiI or DiO in M9 for 2 hours. Animals were then centrifuged at 10,000 rpm for 30 seconds and transferred to a fresh NGM plate with OP50 to recover before scoring. Animals were immobilized with 2,3-Butanedione monoxime (BDM), mounted on 2% agar pads with a glass coverslip, and visualized at 63x with a Zeiss AxioPlan 2 microscope with X-Cite 120LED Boost High-Power LED illumination. A total of 60 to 77 animals were scored per condition across 3-5 independent trials by observers blinded as to genotype.
Statistical Analysis
Prism 10 software was used for statistical analysis and graphics. Statistical values in panel C were calculated with one-way ANOVA and Tukey's multiple-comparisons tests. Statistical values in panel D were calculated with unpaired t-tests. Comparisons were made only between animals assayed on the same days. Results were combined into summary panels.
","reagents":"Strain list
Strain Name | Referenced in paper as | Genotype | Source |
+ | CGC | ||
Tau (high) | bkIs144 [aex-3p::Tau(WT 4R1N); myo-2p::GFP] V | Taylor et al., 2018 | |
Tau (low) | bkIs1441 [aex-3p::Tau(WT 4R1N); myo-2p::dsRED] IV | Walherr et al., 2019 | |
Tau (High); spop-1 (Δ) | spop-1(dr172) III; bkIs144 [aex-3p::Tau(WT 4R1N); myo-2p::GFP] V | This study | |
Tau (low); spop-1 (Δ) | spop-1(bk3107) III; bkIs1441 [aex-3p::Tau(WT 4R1N); myo-2p::GFP] IV | Kow et al., 2023 | |
Tau(V337M) | Kraemer et al., 2003 | ||
Tau(M337V); spop-1(R414*) | bkIs10[Paex-3::Tau V337M, pmyo-2::GFP] III; spop-1(bk4000) III | Eck et al., 2022 | |
TDP-43(A315T) | Liachko et al., 2010 | ||
TDP-43(M337V) | Liachko et al., 2010 |
Primer List
Primer Name | Sequence |
spop-1_F_external | AACCTGCCTCACAACTCATT |
spop-1_R_external | TGTAACCCTTCTGCTCATCATC |
spop-1_F_internal | CTGTGGTAGCCGAAACAGTAA |
Reagent List
Reagent | Source |
1,1'-Dioctadecyl-3,3,3',3'-Tetramethylindocarbocyanine Perchlorate (DiI) | D-282 - Molecular Probes |
3,3'-Dioctadecyloxacarbocyanine Perchlorate (DiO) | D275 - Invitrogen |
2,3-Butanedione monoxime (BDM) | B0753 - Sigma Aldrich |
1x M9 + 1mM MgSO4 | WormBook recipe |
Taq DNA Polymerase with Standard Taq Buffer | M0480X - New England Biolabs |
dNTP Mix | R0192 - ThermoFisher |
Frontotemporal dementia (FTD) is characterized by progressive cognitive decline due to atrophy of the frontal and temporal cortical neurons. Here, we focus on FTD-Tau and FTD-TDP, characterized by the accumulation of tau and TDP-43 proteins, respectively. Importantly, aberrant processing of these proteins is also associated with neurodegeneration in Amyotrophic Lateral Sclerosis (ALS) (Arai et al., 2006, Neumann et al., 2006, Agnello et al., 2021, Latimer et al., 2022, Abu-Rumeileh et al., 2025). Approximately 15% of FTD patients present with ALS, and 15% of ALS patients develop FTD, with up to 50% having cognitive symptoms (Lomen-Hoerth et al., 2002, Lomen-Hoerth et al., 2003, Burrell et al., 2016, Saxon et al., 2017). The pathological overlap of ALS and FTD suggests common mechanisms that may inform treatments to both diseases.
In ALS/FTD patients, glutamatergic cortical neurons are selectively vulnerable (Ferrer, 1999, Seeley, 2008). Previously described C. elegans models of ALS/FTD display locomotor defects, characteristic protein aggregation, and GABAergic neuron loss (Kraemer et al., 2003, Liachko et al. 2010, Taylor et al., 2018, Waldherr et al., 2019); however, the integrity of glutamatergic neurons has not yet been thoroughly explored in these models. Here, we assess glutamatergic neuron degeneration using a dye-filling assay.
Dye-filling is classically used to evaluate the structural integrity of glutamatergic sensory neurons in C. elegans. Eight bilateral pairs of chemosensory neurons–12 amphid neurons (ADF, ASH, ASI, ASJ, ASK, and ADL) in the head and four phasmid neurons (PHA and PHB) in the tail–have exposed cilia endings that can take up lipophilic fluorescent dyes from the environment (Hedgecock et al., 1985) (Fig. 1A). Successful dye uptake indicates intact sensory cilia, neuronal structure and survival; failure to dye-fill usually indicates degeneration of the neuronal processes and/or cilia, or cell death (Fig. 1A). Dye-filling is an efficient readout of glutamatergic neuron integrity and a simple assay for investigation of underlying mechanisms. In this study, we evaluate dye-filling defects in the glutamatergic neurons of adult animals from C. elegans ALS/FTD models, as well as examine the impact of spop-1, a previously described modifier gene, on this degeneration.
Tau model animals have dye-filling defects suppressed by spop-1 loss of function
Alternative splicing, hyperphosphorylation and accumulation of tau is a prominent feature of FTD, occurring in up to 50% of patients, and pathological tau is a biomarker for ALS (Stevens et al., 2019, Agnello et al., 2021, Abu-Rumeileh et al., 2025). To understand if glutamatergic neurons are vulnerable to tau toxicity, we examined three previously characterized C. elegans models of tauopathy. Two of the models express the wild-type 4R1N isoform of human tau pan-neuronally at different expression levels (one high and one low, Fig. 1B). Animals from both strains exhibit tau accumulation, locomotor defects, and GABAergic neuron loss (Benbow et al., 2020, Eck et al., 2022). No degeneration of glutamatergic amphid neurons was observed in these models (Benbow et al., 2020). We examined the phasmid tail neurons in both models using dye-filling, and observed neurodegeneration, which was more severe at higher tau expression levels (Fig. 1C). We also examined a C. elegans model expressing the FTD patient variant tau V337M (Fig. 1B, Kraemer et al., 2003), in which we also observed dye-filling defects (Fig. 1C). We have not examined larval animals, so the defects we observe may be developmental and not caused by age-related degenerative processes. Combined, these results demonstrate that glutamatergic neurons are defective in C. elegans tauopathy models, and that phasmid glutamatergic neurons are more susceptible to human tau toxicity than amphid neurons.
Genetic modifiers can reveal molecular mechanisms critical for neurodegeneration. If neurodegeneration of two different models is suppressed by loss of the same modifier gene, then the models likely share common molecular pathways involved in neurodegeneration. Loss of the conserved nuclear E3 ubiquitin ligase adaptor protein encoded by spop-1 suppresses developmental arrest and age-dependent paralysis in a C. elegans C9orf72 dipeptide toxicity model of ALS (Snoznik et al., 2021). Loss of spop-1 also suppresses GABAergic neurodegeneration, decreases accumulation of phosphorylated tau and extends life span in the Tau(high) model (Eck et al., 2022). We found that loss of spop-1 suppresses glutamatergic neurodegeneration in all three tau models (Fig. 1C). Normally, SPOP-1 binds to the ubiquitin ligase CUL-3 and delivers substrates to the ubiquitin-protease pathway (Kwon et al., 2006). It remains unknown how spop-1 loss suppresses tau-mediated degeneration, but our results, combined with previous studies, suggest a shared molecular mechanism is at work in C. elegans sensory and motor neurons.
TDP-43 model animals do not have strong dye-filling defects
TARDBP variants cause ~3% of ALS cases, and TDP-43 accumulation is a common hallmark of both ALS and FTD (Majumder et al., 2018, Balendra et al., 2025). Two commonly studied patient variants–A315T and M337V–cause the protein to mislocalize from the nucleus to the cytoplasm, where it aggregates (Stallings et al., 2010). In C. elegans TDP-43(A315T) and TDP-43(M337V) models (Fig. 1B), insoluble TDP-43 accumulates in ventral nerve cord neurons (Liachko et al., 2010). Animals also show GABAergic neuron degeneration and exhibit severe, progressive locomotor impairment (Liachko et al., 2010). We observed no dye-filling defects in the phasmid neurons of TDP-43(A315T) animals and only minor dye-filling defects TDP-43(M337V) animals (Fig. 1D). Because these dye-filling defects were small (<10% loss) and not seen in both TDP-43(A315T) and TDP-43(M337V) models, we did not examine the impact of spop-1 loss.
Summary
We have established that expression of wild-type human 4R1N and mutant human V337M tau each cause dye-filling defects in C. elegans glutamatergic neurons. The degeneration observed in Tau (low) and Tau (high) models correlates with tau expression levels. Additionally, loss of the genetic modifier spop-1 suppresses tau-induced glutamatergic neuron defects. This suggests that pathological tau may cause glutamatergic neuron defects via the same mechanisms by which it causes other defects. Further investigation is needed to determine why spop-1 is required in tau-driven degeneration. Finally, defective glutamatergic neurons are not seen across all C. elegans ALS/FTD models. Glutamatergic neurons remain intact in TDP-43 models, suggesting a mechanistic divergence between tau and TDP-43 pathology.
","references":[{"reference":"Abu Rumeileh S, Scholle L, Mensch A, Grosskopf H, Ratti A, Kolsch A, et al., Otto M. 2025. Phosphorylated tau 181 and 217 are elevated in serum and muscle of patients with amyotrophic lateral sclerosis. Nature Communications. 16: 2019.","pubmedId":"","doi":"10.1038/s41467-025-57144-7"},{"reference":"Agnello L, Colletti T, Lo Sasso B, Vidali M, Spataro R, Gambino CM, et al., Ciaccio M. 2021. Tau protein as a diagnostic and prognostic biomarker in amyotrophic lateral sclerosis. European Journal of Neurology. 28: 1868.","pubmedId":"","doi":"10.1111/ene.14789"},{"reference":"Arai T, Hasegawa M, Akiyama H, Ikeda K, Nonaka T, Mori H, et al., Oda T. 2006. TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochemical and Biophysical Research Communications. 351: 602.","pubmedId":"","doi":"10.1016/j.bbrc.2006.10.093"},{"reference":"Balendra R, Sreedharan J, Hallegger M, Luisier R, Lashuel HA, Gregory JM, Patani R. 2025. Amyotrophic lateral sclerosis caused by TARDBP mutations: from genetics to TDP-43 proteinopathy. The Lancet. Neurology. 24: 456.","pubmedId":"","doi":"10.1016/S1474-4422(25)00109-7"},{"reference":"Benbow SJ, Strovas TJ, Darvas M, Saxton A, Kraemer BC. 2020. Synergistic toxicity between tau and amyloid drives neuronal dysfunction and neurodegeneration in transgenic C. elegans. Human Molecular Genetics. 29: 495.","pubmedId":"","doi":"10.1093/hmg/ddz319"},{"reference":"Burrell JR, Halliday GM, Kril JJ, Ittner LM, Gotz J, Kiernan MC, Hodges JR. 2016. The frontotemporal dementia-motor neuron disease continuum. The Lancet. 388: 919.","pubmedId":"","doi":"10.1016/S0140-6736(16)00737-6"},{"reference":"Eck RJ, Kow RL, Black AH, Liachko NF, Kraemer BC. 2023. 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Neurodegeneration and defective neurotransmission in a Caenorhabditis elegans model of tauopathy. Proceedings of the National Academy of Sciences of the United States of America. 100: 9980.","pubmedId":"","doi":"10.1073/pnas.1533448100"},{"reference":"Kwon JE, La M, Oh KH, Oh YM, Kim GR, Seol JH, et al., Chung CH. 2006. BTB Domain-containing Speckle-type POZ Protein (SPOP) Serves as an Adaptor of Daxx for Ubiquitination by Cul3-based Ubiquitin Ligase*. Journal of Biological Chemistry. 281: 12664.","pubmedId":"","doi":"10.1074/jbc.M600204200"},{"reference":"Latimer CS, Stair JG, Hincks JC, Currey HN, Bird TD, Keene CD, Kraemer BC, Liachko NF. 2022. TDP-43 promotes tau accumulation and selective neurotoxicity in bigenic Caenorhabditis elegans. Disease Models & Mechanisms. 15: dmm049323.","pubmedId":"","doi":"10.1242/dmm.049323"},{"reference":"Liachko NF, Guthrie CR, Kraemer BC. 2010. Phosphorylation Promotes Neurotoxicity in a Caenorhabditis elegans Model of TDP-43 Proteinopathy. The Journal of Neuroscience. 30: 16208.","pubmedId":"","doi":"10.1523/JNEUROSCI.2911-10.2010"},{"reference":"Lomen Hoerth C, Anderson T, Miller B. 2002. The overlap of amyotrophic lateral sclerosis and frontotemporal dementia. Neurology. 59: 1077.","pubmedId":"","doi":"10.1212/WNL.59.7.1077"},{"reference":"Lomen Hoerth C, Murphy J, Langmore S, Kramer JH, Olney RK, Miller B. 2003. Are amyotrophic lateral sclerosis patients cognitively normal?. Neurology. 60: 1094.","pubmedId":"","doi":"10.1212/01.WNL.0000055861.95202.8D"},{"reference":"Majumder V, Gregory JM, Barria MA, Green A, Pal S. 2018. TDP-43 as a potential biomarker for amyotrophic lateral sclerosis: a systematic review and meta-analysis. BMC Neurology. 18: 90.","pubmedId":"","doi":"10.1186/s12883-018-1091-7"},{"reference":"Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, et al., Lee VMY. 2006. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. 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Proceedings of the National Academy of Sciences of the United States of America. 118: e2104664118.","pubmedId":"","doi":"10.1073/pnas.2104664118"},{"reference":"Stallings NR, Puttaparthi K, Luther CM, Burns DK, Elliott JL. 2010. Progressive motor weakness in transgenic mice expressing human TDP-43. Neurobiology of Disease. 40: 404.","pubmedId":"","doi":"10.1016/j.nbd.2010.06.017"},{"reference":"Stevens CH, Guthrie NJ, Van Roijen M, Halliday GM, Ooi L. 2019. Increased Tau Phosphorylation in Motor Neurons From Clinically Pure Sporadic Amyotrophic Lateral Sclerosis Patients. Journal of Neuropathology and Experimental Neurology. 78: 605.","pubmedId":"","doi":"10.1093/jnen/nlz041"},{"reference":"Taylor LM, Mc Millan PJ, Liachko NF, Timothy J Strovas, Ghetti B, Bird TD, Keene CD, Kraemer BC. 2018. Pathological phosphorylation of tau and TDP-43 by TTBK1 and TTBK2 drives neurodegeneration. Molecular Neurodegeneration. 13: 7.","pubmedId":"","doi":"10.1186/s13024-018-0237-9"},{"reference":"Waldherr SM, Strovas TJ, Vadset TA, Liachko NF, Kraemer BC. 2019. Constitutive XBP-1s-mediated activation of the endoplasmic reticulum unfolded protein response protects against pathological tau. Nature Communications. 10: 4443.","pubmedId":"","doi":"10.1038/s41467-019-12070-3"}],"title":"Glutamatergic neuron degeneration in C. elegans models of Frontotemporal Dementia and Amyotrophic Lateral Sclerosis
","reviews":[{"reviewer":{"displayName":"Cindy Voisine"},"openAcknowledgement":false,"status":{"submitted":true}}],"curatorReviews":[{"curator":{"displayName":"Gary Craig Schindelman"},"openAcknowledgement":false,"submitted":null},{"curator":{"displayName":"Ranjana Kishore"},"openAcknowledgement":false,"submitted":null},{"curator":{"displayName":"KJ Yook"},"openAcknowledgement":false,"submitted":null}]},{"id":"28c5e58a-089c-4fc0-90db-cdf3e0c2398c","decision":"accept","abstract":"Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) overlap considerably in genetic origin and pathology. Multiple C. elegans models of ALS/FTD have been developed, but the integrity of glutamatergic neurons in these models has not been thoroughly evaluated. Here, we report degeneration of glutamatergic phasmid neurons in animals expressing either wild-type or disease variant V337M human tau, and mild degeneration in animals expressing disease variant M337V human TDP-43. Defects caused by ectopic expression of tau were suppressed by loss of the known modifier, spop-1, suggesting that SPOP-1-dependent pathways are also involved in glutamatergic neuron degeneration.
","acknowledgements":"Strains were provided by the CGC (funded by NIH Office of Research Infrastructure Programs, P40 OD010440), National BioResources Project of Japan. We also thank Dr. Brian Kraemer (Univ. of Washington) for providing previously published strains.
","authors":[{"affiliations":["Brown University, Providence, RI, United States","Carney Institute for Brain Science, Providence, RI, United States"],"departments":["Neuroscience",""],"credit":["conceptualization","formalAnalysis","investigation","methodology","validation","visualization","writing_originalDraft"],"email":"lexi-amber_hassell@brown.edu","firstName":"Lexi-Amber","lastName":"Hassell","submittingAuthor":true,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":"0000-0002-9921-0088"},{"affiliations":["Brown University, Providence, RI, United States"],"departments":["Neuroscience"],"credit":["investigation","writing_reviewEditing"],"email":"mika_gallati@alumni.brown.edu","firstName":"Mika","lastName":"Gallati","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":"0000-0001-8980-5814"},{"affiliations":["Brown University, Providence, RI, United States"],"departments":["Neuroscience"],"credit":["investigation","writing_reviewEditing","visualization"],"email":"monica_thoma@brown.edu","firstName":"Monica","lastName":"Thoma","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["Brown University, Providence, RI, United States"],"departments":["Neuroscience"],"credit":["investigation","writing_originalDraft"],"email":"selamawit_asfaw@alumni.brown.edu","firstName":"Selamawit","lastName":"Asfaw","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["Brown University, Providence, RI, United States","Carney Institute for Brain Science, Providence, RI, United States"],"departments":["Neuroscience",""],"credit":["conceptualization","fundingAcquisition","methodology","project","supervision","writing_reviewEditing"],"email":"anne_hart@brown.edu","firstName":"Anne Church","lastName":"Hart","submittingAuthor":false,"correspondingAuthor":true,"equalContribution":false,"WBId":null,"orcid":"0000-00017239-4350"}],"awards":[],"conflictsOfInterest":"The authors declare that there are no conflicts of interest present.
","dataTable":{"url":null},"extendedData":[],"funding":"Supported in part by NIH R21NS116254 (ACH). MT was supported by the Undergraduate Teaching Research Award. LAH was supported by the Predoctoral Training Program in Biological Data Science (NIH T32 GM149433) and the Interdisciplinary Predoctoral Neuroscience Training Program in the Neuroscience Graduate Program (NIH T32 MH020068).
","image":{"url":"https://portal.micropublication.org/uploads/050a5fea746698fbe29038554c2e8af7.png"},"imageCaption":"A) Four phasmid neurons in the tail dye-fill when intact. Degenerated neurons fail to dye-fill. B) This study uses animals with transgenes expressing hTau WT, hTau V337M, hTDP-43 A315T, and hTDP-43 M337V under pan-neuronal promoters. C) All animals expressing hTau have dye-filling defects suppressed by spop-1 loss of function (Δ = deletion allele, spop-1(dr172); R414* = early stop codon, spop-1(bk4000)). Statistical values were calculated by one-way ANOVA multiple comparison tests. Statistical comparisons between N2 and Tau(low), Tau(high), or Tau(V337M) were made using only animals scored in the same trials. These were combined to make one summary panel shown here. Not shown: spop-1 loss rescues Tau(low) and Tau(V337M) back to WT, but not Tau(high) (p<0.01). D) Animals expressing TDP-43(A315T) do not have dye-filling defects, whereas animals expressing TDP-43(M337V) have minor, but significant dye-filling defects compared to N2 animals trialed on the same days. Statistical values were calculated by unpaired t-tests. ns = p>0.05, * = p<0.05, ** = p<0.01, *** = p<0.001, **** =p<0.0001
","imageTitle":"C. elegans models of ALS/FTD have varying degrees of dye-filling defects
","methods":"Strains were maintained at 20˚C on NGM plates and OP50 E. coli.
Dye-filling
L4 animals were picked 18 hours before dye-filling to seeded NGM plates. After 18 hours, Day 1 adults were suspended on a shaker in 500 uL of 0.012 mg/mL DiI or DiO in M9 for 2 hours. Animals were then centrifuged at 10,000 rpm for 30 seconds and transferred to a fresh NGM plate with OP50 to recover before scoring. Animals were immobilized with 2,3-Butanedione monoxime (BDM), mounted on 2% agar pads with a glass coverslip, and visualized at 63x with a Zeiss AxioPlan 2 microscope with X-Cite 120LED Boost High-Power LED illumination. A total of 60 to 77 animals were scored per condition across 3-5 independent trials by observers blinded as to genotype.
Statistical Analysis
Prism 10 software was used for statistical analysis and graphics. Statistical values in panel C were calculated with one-way ANOVA and Tukey's multiple-comparisons tests. Statistical values in panel D were calculated with unpaired t-tests. Comparisons were made only between animals assayed on the same days. Results were combined into summary panels.
","reagents":"Strain list
Strain Name | Referenced in paper as | Genotype | Source |
+ | CGC | ||
Tau (high) | bkIs144 [aex-3p::Tau(WT 4R1N); myo-2p::GFP] V | Taylor et al., 2018 | |
Tau (low) | bkIs1441 [aex-3p::Tau(WT 4R1N); myo-2p::dsRED] IV | Walherr et al., 2019 | |
Tau (High); spop-1 (Δ) | spop-1(dr172) III; bkIs144 [aex-3p::Tau(WT 4R1N); myo-2p::GFP] V | This study | |
Tau (low); spop-1 (Δ) | spop-1(bk3107) III; bkIs1441 [aex-3p::Tau(WT 4R1N); myo-2p::GFP] IV | Kow et al., 2023 | |
Tau(V337M) | Kraemer et al., 2003 | ||
Tau(M337V); spop-1(R414*) | bkIs10[Paex-3::Tau V337M, pmyo-2::GFP] III; spop-1(bk4000) III | Eck et al., 2022 | |
TDP-43(A315T) | Liachko et al., 2010 | ||
TDP-43(M337V) | Jadhav et al., 2026 |
Primer List
Primer Name | Sequence |
spop-1_F_external | AACCTGCCTCACAACTCATT |
spop-1_R_external | TGTAACCCTTCTGCTCATCATC |
spop-1_F_internal | CTGTGGTAGCCGAAACAGTAA |
Reagent List
Reagent | Source |
1,1'-Dioctadecyl-3,3,3',3'-Tetramethylindocarbocyanine Perchlorate (DiI) | D-282 - Molecular Probes |
3,3'-Dioctadecyloxacarbocyanine Perchlorate (DiO) | D275 - Invitrogen |
2,3-Butanedione monoxime (BDM) | B0753 - Sigma Aldrich |
1x M9 + 1mM MgSO4 | WormBook recipe |
Taq DNA Polymerase with Standard Taq Buffer | M0480X - New England Biolabs |
dNTP Mix | R0192 - ThermoFisher |
Frontotemporal dementia (FTD) is characterized by progressive cognitive decline due to atrophy of the frontal and temporal cortical neurons. Here, we focus on FTD-Tau and FTD-TDP, characterized by the accumulation of tau and TDP-43 proteins, respectively. Importantly, aberrant processing of these proteins is also associated with neurodegeneration in Amyotrophic Lateral Sclerosis (ALS) (Arai et al., 2006, Neumann et al., 2006, Agnello et al., 2021, Latimer et al., 2022, Abu-Rumeileh et al., 2025). Approximately 15% of FTD patients present with ALS, and 15% of ALS patients develop FTD, with up to 50% having cognitive symptoms (Lomen-Hoerth et al., 2002, Lomen-Hoerth et al., 2003, Burrell et al., 2016, Saxon et al., 2017). The pathological overlap of ALS and FTD suggests common mechanisms that may inform treatments to both diseases.
In ALS/FTD patients, glutamatergic cortical neurons are selectively vulnerable (Ferrer, 1999, Seeley, 2008). Previously described C. elegans models of ALS/FTD display locomotor defects, characteristic protein aggregation, and GABAergic neuron loss (Kraemer et al., 2003, Liachko et al. 2010, Taylor et al., 2018, Waldherr et al., 2019, Jadhav et al., 2026); however, the integrity of glutamatergic neurons has not yet been thoroughly explored in these models. Here, we assess glutamatergic neuron degeneration using a dye-filling assay.
Dye-filling is classically used to evaluate the structural integrity of glutamatergic sensory neurons in C. elegans. Eight bilateral pairs of chemosensory neurons–12 amphid neurons (ADF, ASH, ASI, ASJ, ASK, and ADL) in the head and four phasmid neurons (PHA and PHB) in the tail–have exposed cilia endings that can take up lipophilic fluorescent dyes from the environment (Hedgecock et al., 1985) (Fig. 1A). Successful dye uptake indicates intact sensory cilia, neuronal structure and survival; failure to dye-fill usually indicates degeneration of the neuronal processes and/or cilia, or cell death (Fig. 1A). Dye-filling is an efficient readout of glutamatergic neuron integrity and a simple assay for investigation of underlying mechanisms. In this study, we evaluate dye-filling defects in the glutamatergic neurons of adult animals from C. elegans ALS/FTD models, as well as examine the impact of spop-1, a previously described modifier gene, on this degeneration.
Tau model animals have dye-filling defects suppressed by spop-1 loss of function
Alternative splicing, hyperphosphorylation and accumulation of tau is a prominent feature of FTD, occurring in up to 50% of patients, and pathological tau is a biomarker for ALS (Stevens et al., 2019, Agnello et al., 2021, Abu-Rumeileh et al., 2025). To understand if glutamatergic neurons are vulnerable to tau toxicity, we examined three previously characterized C. elegans models of tauopathy. Two of the models express the wild-type 4R1N isoform of human tau pan-neuronally at different expression levels (one high and one low, Fig. 1B). Animals from both strains exhibit tau accumulation, locomotor defects, and GABAergic neuron loss (Benbow et al., 2020, Eck et al., 2022). No degeneration of glutamatergic amphid neurons was observed in these models (Benbow et al., 2020). We examined the phasmid tail neurons in both models using dye-filling, and observed neurodegeneration, which was more severe at higher tau expression levels (Fig. 1C). We also examined a C. elegans model expressing the FTD patient variant tau V337M (Fig. 1B, Kraemer et al., 2003), in which we also observed dye-filling defects (Fig. 1C). We have not examined larval animals, so the defects we observe may be developmental and not caused by age-related degenerative processes. Combined, these results demonstrate that glutamatergic neurons are defective in C. elegans tauopathy models, and that phasmid glutamatergic neurons are more susceptible to human tau toxicity than amphid neurons.
Genetic modifiers can reveal molecular mechanisms critical for neurodegeneration. If neurodegeneration of two different models is suppressed by loss of the same modifier gene, then the models likely share common molecular pathways involved in neurodegeneration. Loss of the conserved nuclear E3 ubiquitin ligase adaptor protein encoded by spop-1 suppresses developmental arrest and age-dependent paralysis in a C. elegans C9orf72 dipeptide toxicity model of ALS (Snoznik et al., 2021). Loss of spop-1 also suppresses GABAergic neurodegeneration, decreases accumulation of phosphorylated tau and extends life span in the Tau(high) model (Eck et al., 2022). We found that loss of spop-1 suppresses glutamatergic neurodegeneration in all three tau models (Fig. 1C). Normally, SPOP-1 binds to the ubiquitin ligase CUL-3 and delivers substrates to the ubiquitin-protease pathway (Kwon et al., 2006). It remains unknown how spop-1 loss suppresses tau-mediated degeneration, but our results, combined with previous studies, suggest a shared molecular mechanism is at work in C. elegans sensory and motor neurons.
TDP-43 model animals do not have strong dye-filling defects
TARDBP variants cause ~3% of ALS cases, and TDP-43 accumulation is a common hallmark of both ALS and FTD (Majumder et al., 2018, Balendra et al., 2025). Two commonly studied patient variants–A315T and M337V–cause the protein to mislocalize from the nucleus to the cytoplasm, where it aggregates (Stallings et al., 2010). In C. elegans TDP-43(A315T) and TDP-43(M337V) models (Fig. 1B), insoluble TDP-43 accumulates in ventral nerve cord neurons (Liachko et al., 2010). Animals also show GABAergic neuron degeneration and exhibit severe, progressive locomotor impairment (Liachko et al., 2010, Jadhav et al., 2026). We observed no dye-filling defects in the phasmid neurons of TDP-43(A315T) animals and only minor dye-filling defects TDP-43(M337V) animals (Fig. 1D). This difference might arise from different expression levels from the transgene promoters or from a difference in toxicity of the expressed protein. Because these dye-filling defects were small (<10% loss) and inconsistent between TDP-43(A315T) and TDP-43(M337V) models, we did not examine the impact of spop-1 loss.
Summary
We have established that expression of wild-type human 4R1N and mutant human V337M tau each cause dye-filling defects in C. elegans glutamatergic neurons. The degeneration observed in Tau (low) and Tau (high) models correlates with tau expression levels. Additionally, loss of the genetic modifier spop-1 suppresses tau-induced glutamatergic neuron defects. This suggests that pathological tau may cause glutamatergic neuron defects via the same mechanisms by which it causes other defects. Further investigation is needed to determine why spop-1 is required in tau-driven degeneration. Finally, defective glutamatergic neurons are not seen in all C. elegans ALS/FTD models. Glutamatergic neurons were intact in one of the two TDP-43 models examined. The results presented here define glutamatergic neuron defects that can be used to understand the cellular mechanisms underlying neurodegeneration in C. elegans models of FTD and ALS.
","references":[{"reference":"Abu Rumeileh S, Scholle L, Mensch A, Grosskopf H, Ratti A, Kolsch A, et al., Otto M. 2025. Phosphorylated tau 181 and 217 are elevated in serum and muscle of patients with amyotrophic lateral sclerosis. Nature Communications. 16: 2019.","pubmedId":"","doi":"10.1038/s41467-025-57144-7"},{"reference":"Agnello L, Colletti T, Lo Sasso B, Vidali M, Spataro R, Gambino CM, et al., Ciaccio M. 2021. Tau protein as a diagnostic and prognostic biomarker in amyotrophic lateral sclerosis. European Journal of Neurology. 28: 1868.","pubmedId":"","doi":"10.1111/ene.14789"},{"reference":"Arai T, Hasegawa M, Akiyama H, Ikeda K, Nonaka T, Mori H, et al., Oda T. 2006. TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochemical and Biophysical Research Communications. 351: 602.","pubmedId":"","doi":"10.1016/j.bbrc.2006.10.093"},{"reference":"Balendra R, Sreedharan J, Hallegger M, Luisier R, Lashuel HA, Gregory JM, Patani R. 2025. Amyotrophic lateral sclerosis caused by TARDBP mutations: from genetics to TDP-43 proteinopathy. The Lancet. Neurology. 24: 456.","pubmedId":"","doi":"10.1016/S1474-4422(25)00109-7"},{"reference":"Benbow SJ, Strovas TJ, Darvas M, Saxton A, Kraemer BC. 2020. Synergistic toxicity between tau and amyloid drives neuronal dysfunction and neurodegeneration in transgenic C. elegans. Human Molecular Genetics. 29: 495.","pubmedId":"","doi":"10.1093/hmg/ddz319"},{"reference":"Burrell JR, Halliday GM, Kril JJ, Ittner LM, Gotz J, Kiernan MC, Hodges JR. 2016. The frontotemporal dementia-motor neuron disease continuum. The Lancet. 388: 919.","pubmedId":"","doi":"10.1016/S0140-6736(16)00737-6"},{"reference":"Eck RJ, Kow RL, Black AH, Liachko NF, Kraemer BC. 2023. SPOP loss of function protects against tauopathy. Proceedings of the National Academy of Sciences of the United States of America. 120: e2207250120.","pubmedId":"","doi":"10.1073/pnas.2207250120"},{"reference":"Ferrer I. 1999. Neurons and Their Dendrites in Frontotemporal Dementia. Dementia and Geriatric Cognitive Disorders. 10: 55.","pubmedId":"","doi":"10.1159/000051214"},{"reference":"Hedgecock EM, Culotti JG, Thomson JN, Perkins LA. 1985. Axonal guidance mutants of Caenorhabditis elegans identified by filling sensory neurons with fluorescein dyes. Developmental Biology. 111: 158.","pubmedId":"","doi":"10.1016/0012-1606(85)90443-9"},{"reference":"Jadhav VS, Kow RL, Beale AD, Baum M, McMillan PJ, Latimer CS, Liachko NF, Kraemer BC. 2026. Loss of\n
Glutamatergic neuron degeneration in C. elegans models of Frontotemporal Dementia and Amyotrophic Lateral Sclerosis
","reviews":[],"curatorReviews":[{"curator":{"displayName":"Gary Craig Schindelman"},"openAcknowledgement":false,"submitted":"1786659204532"},{"curator":{"displayName":"Ranjana Kishore"},"openAcknowledgement":true,"submitted":"1786650167363"},{"curator":{"displayName":"KJ Yook"},"openAcknowledgement":false,"submitted":"1786990685740"}]},{"id":"c09e8b33-6a72-48bc-b5bb-24f3ac22b3ec","decision":"publish","abstract":"Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) overlap considerably in genetic origin and pathology. Multiple C. elegans models of ALS/FTD have been developed, but the integrity of glutamatergic neurons in these models has not been thoroughly evaluated. Here, we report degeneration of glutamatergic phasmid neurons in animals expressing either wild-type or disease variant V337M human tau, and mild degeneration in animals expressing disease variant M337V human TDP-43. Defects caused by ectopic expression of tau were suppressed by loss of the known modifier, spop-1, suggesting that SPOP-1-dependent pathways are also involved in glutamatergic neuron degeneration.
","acknowledgements":"Some strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). We also thank Dr. Brian Kraemer (Univ. of Washington) for providing previously published strains.
","authors":[{"affiliations":["Brown University, Providence, RI, United States","Carney Institute for Brain Science, Providence, RI, United States"],"departments":["Neuroscience",""],"credit":["conceptualization","formalAnalysis","investigation","methodology","validation","visualization","writing_originalDraft"],"email":"lexi-amber_hassell@brown.edu","firstName":"Lexi-Amber","lastName":"Hassell","submittingAuthor":true,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":"0000-0002-9921-0088"},{"affiliations":["Brown University, Providence, RI, United States"],"departments":["Neuroscience"],"credit":["investigation","writing_reviewEditing"],"email":"mika_gallati@alumni.brown.edu","firstName":"Mika","lastName":"Gallati","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":"0000-0001-8980-5814"},{"affiliations":["Brown University, Providence, RI, United States"],"departments":["Neuroscience"],"credit":["investigation","writing_reviewEditing","visualization"],"email":"monica_thoma@brown.edu","firstName":"Monica","lastName":"Thoma","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["Brown University, Providence, RI, United States"],"departments":["Neuroscience"],"credit":["investigation","writing_originalDraft"],"email":"selamawit_asfaw@alumni.brown.edu","firstName":"Selamawit","lastName":"Asfaw","submittingAuthor":false,"correspondingAuthor":false,"equalContribution":false,"WBId":null,"orcid":null},{"affiliations":["Brown University, Providence, RI, United States","Carney Institute for Brain Science, Providence, RI, United States"],"departments":["Neuroscience",""],"credit":["conceptualization","fundingAcquisition","methodology","project","supervision","writing_reviewEditing"],"email":"anne_hart@brown.edu","firstName":"Anne Church","lastName":"Hart","submittingAuthor":false,"correspondingAuthor":true,"equalContribution":false,"WBId":null,"orcid":"0000-00017239-4350"}],"awards":[],"conflictsOfInterest":"The authors declare that there are no conflicts of interest present.
","dataTable":{"url":null},"extendedData":[],"funding":"Research supported in part by NIH R21NS116254. MT was supported by the Undergraduate Teaching Research Award. LAH was supported by the Predoctoral Training Program in Biological Data Science (NIH T32 GM149433) and the Interdisciplinary Predoctoral Neuroscience Training Program in the Neuroscience Graduate Program (NIH T32 MH020068).
","image":{"url":"https://portal.micropublication.org/uploads/ffea206141ba6b7f829a78b38df14707.png"},"imageCaption":"A) Four phasmid neurons in the tail dye-fill when intact. Degenerated neurons fail to dye-fill. B) This study uses animals with transgenes expressing hTau WT, hTau V337M, hTDP-43 A315T, and hTDP-43 M337V under pan-neuronal promoters. C) All animals expressing hTau have dye-filling defects suppressed by spop-1 loss of function (Δ = deletion allele, spop-1(dr172); R414* = early stop codon, spop-1(bk4000)). Statistical values were calculated by one-way ANOVA multiple comparison tests. Statistical comparisons between N2 and Tau(low), Tau(high), or Tau(V337M) were made using only animals scored in the same trials. These were combined to make one summary panel shown here. Not shown: spop-1 loss rescues Tau(low) and Tau(V337M) back to WT, but not Tau(high) (p<0.01). D) Animals expressing TDP-43(A315T) do not have dye-filling defects, whereas animals expressing TDP-43(M337V) have minor, but significant dye-filling defects compared to N2 animals trialed on the same days. Statistical values were calculated by unpaired t-tests. ns = p>0.05, * = p<0.05, ** = p<0.01, *** = p<0.001, **** =p<0.0001
","imageTitle":"C. elegans models of ALS/FTD have varying degrees of dye-filling defects
","methods":"Strains were maintained at 20˚C on NGM plates and OP50 E. coli.
Dye-filling
L4 animals were picked 18 hours before dye-filling to seeded NGM plates. After 18 hours, Day 1 adults were suspended on a shaker in 500 uL of DiI or DiO (final concentration 0.012 mg/mL) in M9/0.6% ethanol for 2 hours. Animals were then centrifuged at 10,000 rpm for 30 seconds and transferred to a fresh NGM plate with OP50 to recover before scoring. Animals were immobilized with 2,3-Butanedione monoxime (BDM), mounted on 2% agar pads with a glass coverslip, and visualized at 63x with a Zeiss AxioPlan 2 microscope with X-Cite 120LED Boost High-Power LED illumination. A total of 60 to 77 animals were scored per condition across 3-5 independent trials by observers blinded as to genotype.
Statistical Analysis
Prism 10 software was used for statistical analysis and graphics. Statistical values in panel C were calculated with one-way ANOVA and Tukey's multiple-comparisons tests. Statistical values in panel D were calculated with unpaired t-tests. Comparisons were made only between animals assayed on the same days. Results were combined into summary panels.
","reagents":"Strain list
Strain Name | Referenced in paper as | Genotype | Source |
+ | CGC | ||
Tau (high) | bkIs144 [aex-3p::Tau(WT 4R1N); myo-2p::GFP] V | Taylor et al., 2018 | |
Tau (low) | bkIs1441 [aex-3p::Tau(WT 4R1N); myo-2p::dsRED] IV | Walherr et al., 2019 | |
Tau (High); spop-1 (Δ) | spop-1(dr172) III; bkIs144 [aex-3p::Tau(WT 4R1N); myo-2p::GFP] V | This study | |
Tau (low); spop-1 (Δ) | spop-1(bk3107) III; bkIs1441 [aex-3p::Tau(WT 4R1N); myo-2p::GFP] IV | Kow et al., 2023 | |
Tau(V337M) | Kraemer et al., 2003 | ||
Tau(M337V); spop-1(R414*) | bkIs10[Paex-3::Tau V337M, pmyo-2::GFP] III; spop-1(bk4000) III | Eck et al., 2022 | |
TDP-43(A315T) | Liachko et al., 2010 | ||
TDP-43(M337V) | Jadhav et al., 2026 |
Primer List
Primer Name | Sequence |
spop-1_F_external | AACCTGCCTCACAACTCATT |
spop-1_R_external | TGTAACCCTTCTGCTCATCATC |
spop-1_F_internal | CTGTGGTAGCCGAAACAGTAA |
Reagent List
Reagent | Source |
1,1'-Dioctadecyl-3,3,3',3'-Tetramethylindocarbocyanine Perchlorate (DiI) | D-282 - Molecular Probes |
3,3'-Dioctadecyloxacarbocyanine Perchlorate (DiO) | D275 - Invitrogen |
2,3-Butanedione monoxime (BDM) | B0753 - Sigma Aldrich |
1x M9 + 1mM MgSO4 | WormBook recipe |
Taq DNA Polymerase with Standard Taq Buffer | M0480X - New England Biolabs |
dNTP Mix | R0192 - ThermoFisher |
Frontotemporal dementia (FTD) is characterized by progressive cognitive decline due to atrophy of the frontal and temporal cortical neurons. Here, we focus on FTD-Tau and FTD-TDP, characterized by the accumulation of tau and TDP-43 proteins, respectively. Importantly, aberrant processing of these proteins is also associated with neurodegeneration in Amyotrophic Lateral Sclerosis (ALS) (Arai et al., 2006, Neumann et al., 2006, Agnello et al., 2021, Latimer et al., 2022, Abu-Rumeileh et al., 2025). Approximately 15% of FTD patients present with ALS, and 15% of ALS patients develop FTD, with up to 50% having cognitive symptoms (Lomen-Hoerth et al., 2002, Lomen-Hoerth et al., 2003, Burrell et al., 2016, Saxon et al., 2017). The pathological overlap of ALS and FTD suggests common mechanisms that may inform treatments to both diseases.
In ALS/FTD patients, glutamatergic cortical neurons are selectively vulnerable (Ferrer, 1999, Seeley, 2008). Previously described C. elegans models of ALS/FTD display locomotor defects, characteristic protein aggregation, and GABAergic neuron loss (Kraemer et al., 2003, Liachko et al. 2010, Taylor et al., 2018, Waldherr et al., 2019, Jadhav et al., 2026); however, the integrity of glutamatergic neurons has not yet been thoroughly explored in these models. Here, we assess glutamatergic neuron degeneration using a dye-filling assay.
Dye-filling is classically used to evaluate the structural integrity of glutamatergic sensory neurons in C. elegans. Eight bilateral pairs of chemosensory neurons–twelve amphid neurons (ADF, ASH, ASI, ASJ, ASK, and ADL) in the head and four phasmid neurons (PHA and PHB) in the tail–have exposed cilia endings that can take up lipophilic fluorescent dyes from the environment (Hedgecock et al., 1985) (Fig. 1A). Successful dye uptake indicates intact sensory cilia, neuronal structure and survival; failure to dye-fill usually indicates degeneration of the neuronal processes and/or cilia, or cell death (Fig. 1A). Dye-filling is an efficient readout of glutamatergic neuron integrity and a simple assay for investigation of underlying mechanisms. In this study, we evaluate dye-filling defects in the glutamatergic neurons of adult animals from C. elegans ALS/FTD models, as well as examine the impact of spop-1, a previously described modifier gene, on this degeneration.
Tau model animals have dye-filling defects suppressed by spop-1 loss of function
Alternative splicing, hyperphosphorylation and accumulation of tau is a prominent feature of FTD, occurring in up to 50% of patients, and pathological tau is a biomarker for ALS (Stevens et al., 2019, Agnello et al., 2021, Abu-Rumeileh et al., 2025). To understand if glutamatergic neurons are vulnerable to tau toxicity, we examined three previously characterized C. elegans models of tauopathy. Two of the models express the wild-type 4R1N isoform of human tau pan-neuronally at different expression levels (one high and one low, Fig. 1B). Animals from both strains exhibit tau accumulation, locomotor defects, and GABAergic neuron loss (Benbow et al., 2020, Eck et al., 2022). No degeneration of glutamatergic amphid neurons was observed in these models (Benbow et al., 2020). We examined the phasmid tail neurons in both models using dye-filling, and observed neurodegeneration, which was more severe at higher tau expression levels (Fig. 1C). We also examined a C. elegans model expressing the FTD patient variant tau V337M (Fig. 1B, Kraemer et al., 2003), in which we also observed dye-filling defects (Fig. 1C). We have not examined larval animals, so the defects we observe may be developmental and not caused by age-related degenerative processes. Combined, these results demonstrate that glutamatergic neurons are defective in C. elegans tauopathy models, and that phasmid glutamatergic neurons are more susceptible to human tau toxicity than amphid neurons.
Genetic modifiers can reveal molecular mechanisms critical for neurodegeneration. If neurodegeneration of two different models is suppressed by loss of the same modifier gene, then the models likely share common molecular pathways involved in neurodegeneration. Loss of the conserved nuclear E3 ubiquitin ligase adaptor protein encoded by spop-1 suppresses developmental arrest and age-dependent paralysis in a C. elegans C9orf72 dipeptide toxicity model of ALS (Snoznik et al., 2021). Loss of spop-1 also suppresses GABAergic neurodegeneration, decreases accumulation of phosphorylated tau and extends life span in the Tau(high) model (Eck et al., 2022). We found that loss of spop-1 suppresses glutamatergic neurodegeneration in all three tau models (Fig. 1C). Normally, SPOP-1 binds to the ubiquitin ligase CUL-3 and delivers substrates to the ubiquitin-protease pathway (Kwon et al., 2006). It remains unknown how spop-1 loss suppresses tau-mediated degeneration, but our results, combined with previous studies, suggest a shared molecular mechanism is at work in C. elegans sensory and motor neurons.
TDP-43 model animals do not have strong dye-filling defects
TARDBP variants cause ~3% of ALS cases, and TDP-43 accumulation is a common hallmark of both ALS and FTD (Majumder et al., 2018, Balendra et al., 2025). Two commonly studied patient variants–A315T and M337V–cause the protein to mislocalize from the nucleus to the cytoplasm, where it aggregates (Stallings et al., 2010). In C. elegans TDP-43(A315T) and TDP-43(M337V) models (Fig. 1B), insoluble TDP-43 accumulates in ventral nerve cord neurons (Liachko et al., 2010). Animals also show GABAergic neuron degeneration and exhibit severe, progressive locomotor impairment (Liachko et al., 2010, Jadhav et al., 2026). We observed no dye-filling defects in the phasmid neurons of TDP-43(A315T) animals and only minor dye-filling defects TDP-43(M337V) animals (Fig. 1D). This difference might arise from different expression levels from the transgene promoters or from a difference in toxicity of the expressed protein. Because these dye-filling defects were small (<10% loss) and inconsistent between TDP-43(A315T) and TDP-43(M337V) models, we did not examine the impact of spop-1 loss.
Summary
We have established that expression of wild-type human 4R1N and mutant human V337M tau each cause dye-filling defects in C. elegans glutamatergic neurons. The degeneration observed in Tau(low) and Tau(high) models correlates with tau expression levels. Additionally, loss of the genetic modifier spop-1 suppresses tau-induced glutamatergic neuron defects. This suggests that pathological tau may cause glutamatergic neuron defects via the same mechanisms by which it causes other defects. Further investigation is needed to determine why spop-1 is required in tau-driven degeneration. Finally, defective glutamatergic neurons are not seen in all C. elegans ALS/FTD models. Glutamatergic neurons were intact in one of the two TDP-43 models examined. The results presented here define glutamatergic neuron defects that can be used to understand the cellular mechanisms underlying neurodegeneration in C. elegans models of FTD and ALS.
","references":[{"reference":"Abu Rumeileh S, Scholle L, Mensch A, Grosskopf H, Ratti A, Kolsch A, et al., Otto M. 2025. Phosphorylated tau 181 and 217 are elevated in serum and muscle of patients with amyotrophic lateral sclerosis. Nature Communications. 16: 2019.","pubmedId":"","doi":"10.1038/s41467-025-57144-7"},{"reference":"Agnello L, Colletti T, Lo Sasso B, Vidali M, Spataro R, Gambino CM, et al., Ciaccio M. 2021. Tau protein as a diagnostic and prognostic biomarker in amyotrophic lateral sclerosis. European Journal of Neurology. 28: 1868.","pubmedId":"","doi":"10.1111/ene.14789"},{"reference":"Arai T, Hasegawa M, Akiyama H, Ikeda K, Nonaka T, Mori H, et al., Oda T. 2006. TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochemical and Biophysical Research Communications. 351: 602.","pubmedId":"","doi":"10.1016/j.bbrc.2006.10.093"},{"reference":"Balendra R, Sreedharan J, Hallegger M, Luisier R, Lashuel HA, Gregory JM, Patani R. 2025. Amyotrophic lateral sclerosis caused by TARDBP mutations: from genetics to TDP-43 proteinopathy. The Lancet. Neurology. 24: 456.","pubmedId":"","doi":"10.1016/S1474-4422(25)00109-7"},{"reference":"Benbow SJ, Strovas TJ, Darvas M, Saxton A, Kraemer BC. 2020. Synergistic toxicity between tau and amyloid drives neuronal dysfunction and neurodegeneration in transgenic C. elegans. Human Molecular Genetics. 29: 495.","pubmedId":"","doi":"10.1093/hmg/ddz319"},{"reference":"Burrell JR, Halliday GM, Kril JJ, Ittner LM, Gotz J, Kiernan MC, Hodges JR. 2016. The frontotemporal dementia-motor neuron disease continuum. The Lancet. 388: 919.","pubmedId":"","doi":"10.1016/S0140-6736(16)00737-6"},{"reference":"Eck RJ, Kow RL, Black AH, Liachko NF, Kraemer BC. 2023. SPOP loss of function protects against tauopathy. Proceedings of the National Academy of Sciences of the United States of America. 120: e2207250120.","pubmedId":"","doi":"10.1073/pnas.2207250120"},{"reference":"Ferrer I. 1999. Neurons and Their Dendrites in Frontotemporal Dementia. Dementia and Geriatric Cognitive Disorders. 10: 55.","pubmedId":"","doi":"10.1159/000051214"},{"reference":"Hedgecock EM, Culotti JG, Thomson JN, Perkins LA. 1985. Axonal guidance mutants of Caenorhabditis elegans identified by filling sensory neurons with fluorescein dyes. Developmental Biology. 111: 158.","pubmedId":"","doi":"10.1016/0012-1606(85)90443-9"},{"reference":"Jadhav VS, Kow RL, Beale AD, Baum M, McMillan PJ, Latimer CS, Liachko NF, Kraemer BC. 2026. Loss of\n
Glutamatergic neuron degeneration in C. elegans models of Frontotemporal Dementia and Amyotrophic Lateral Sclerosis
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