Sqstm1 knock-down causes a locomotor phenotype ameliorated by rapamycin in a zebrafish model of ALS/FTLD

Lattante, Serena; de Calbiac, Hortense; Le Ber, Isabelle; Brice, Alexis; Ciura, Sorana; Kabashi, Edor

doi:10.1093/hmg/ddu580

Cited by 90Amyotrophic Lateral Sclerosis ResearchHereditary Neurological DisordersMuscle Physiology and Disorders

Sqstm1 knock-down causes a locomotor phenotype ameliorated by rapamycin in a zebrafish model of ALS/FTLD

Lattante, Serena, de Calbiac, Hortense, Le Ber, Isabelle, Brice, Alexis, Ciura, Sorana, Kabashi, Edor·2015·Human Molecular Genetics

DOI 10.1093/hmg/ddu580

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Abstract

Mutations in SQSTM1, encoding for the protein SQSTM1/p62, have been recently reported in 1-3.5% of patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration (ALS/FTLD). Inclusions positive for SQSTM1/p62 have been detected in patients with neurodegenerative disorders, including ALS/FTLD. In order to investigate the pathogenic mechanisms induced by SQSTM1 mutations in ALS/FTLD, we developed a zebrafish model. Knock-down of the sqstm1 zebrafish ortholog, as well as impairment of its splicing, led to a specific phenotype, consisting of behavioral and axonal anomalies. Here, we report swimming deficits associated with shorter motor neuronal axons that could be rescued by the overexpression of wild-type human SQSTM1. Interestingly, no rescue of the loss-of-function phenotype was observed when overexpressing human SQSTM1 constructs carrying ALS/FTLD-related mutations. Consistent with its role in autophagy regulation, we found increased mTOR levels upon knock-down of sqstm1. Furthermore, treatment of zebrafish embryos with rapamycin, a known inhibitor of the mTOR pathway, yielded an amelioration of the locomotor phenotype in the sqstm1 knock-down model. Our results suggest that loss-of-function of SQSTM1 causes phenotypic features characterized by locomotor deficits and motor neuron axonal defects that are associated with a misregulation of autophagic processes.

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Knockdown of the SQSTM1 ortholog in zebrafish leads to an ALS-like phenotype consisting of locomotor and motor neuron axonal abnormalities, which is rescued by overexpression of wild-type human SQSTM1 or rapamycin.
“Knockdown of the SQSTM1 ortholog in zebrafish leads to an ALS-like phenotype consisting of locomotor and motor neuron axonal abnormalities. Overexpression of wild-type human SQSTM1 or application of the autophagy activator rapamycin rescues these phenotypes [137].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [137]

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Mandrioli, J., D’Amico, R., Zucchi, E., Gessani, A., Fini, N., Fasano, A., Caponnetto, C., Chiò, A., Dalla Bella, E., Lunetta, C., et al. (2018) · Medicine · doi:10.1097/md.0000000000011119 · Cited by 128 · see citing works
Autophagy in health and disease: From molecular mechanisms to therapeutic target
Lu, G. X., Wang, Y., Shi, Y. P., Zhang, Z., Huang, C., He, W., Wang, C., & Shen, H. (2022) · MedComm · doi:10.1002/mco2.150 · Cited by 127 · see citing works
Defining the genetic connection linking amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD)
Lattante, S., Ciura, S., Rouleau, G. A., & Kabashi, E. (2015) · Trends in Genetics · doi:10.1016/j.tig.2015.03.005 · Cited by 125 · see citing works
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Autophagy in Age-Associated Neurodegeneration
Metaxakis, A., Ploumi, C., & Tavernarakis, N. (2018) · Cells · doi:10.3390/cells7050037 · Cited by 121 · see citing works
“Interestingly loss of p62 in zebrafish led to motor neuron defects, similar to ALS symptoms [155].”
Background
The circadian clock regulates autophagy directly through the nuclear hormone receptor Nr1d1/Rev-erbα and indirectly via Cebpb/(C/ebpβ) in zebrafish
Huang, G., Zhang, F.-M., Ye, Q., & Wang, H. (2016) · Autophagy · doi:10.1080/15548627.2016.1183843 · Cited by 104 · see citing works
“S1C, S1D and S1E), likely affected by developmental regulation in zebrafish.(39) Together, these results”
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Advances of Zebrafish in Neurodegenerative Disease: From Models to Drug Discovery
Wang, X., Zhang, J., He, K.-J., Wang, F., & Liu, C. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.713963 · Cited by 106 · see citing works
The genetics of amyotrophic lateral sclerosis: current insights
Kirby, J., Sultan, A. A., Waller, R., & Heath, P. R. (2016) · Degenerative Neurological and Neuromuscular Disease · doi:10.2147/dnnd.s84956 · Cited by 107 · see citing works
Iron and Neurodegeneration: Is Ferritinophagy the Link?
Biasiotto, G., Lorenzo, D. D., Archetti, S., & Zanella, I. (2015) · Molecular Neurobiology · doi:10.1007/s12035-015-9473-y · Cited by 104 · see citing works
ALS-associated KIF5A mutations abolish autoinhibition resulting in a toxic gain of function
Baron, D. M., Fenton, A. R., Sáez-Atiénzar, S., Giampetruzzi, A., Sreeram, A., Shankaracharya, Keagle, P. J., Doocy, V. R., Smith, N. J., Danielson, E., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110598 · Cited by 98 · see citing works
Autophagy receptor defects and ALS-FTLD
Majcher, V., Goode, A., James, V. H., & Layfield, R. (2015) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2015.01.002 · Cited by 91 · see citing works
Role of autophagy in the pathogenesis of amyotrophic lateral sclerosis
Lee, J. K., Shin, J. H., Lee, J. E., & Choi, E.-J. (2015) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2015.08.005 · Cited by 84 · see citing works
Randomized, double-blind, placebo-controlled trial of rapamycin in amyotrophic lateral sclerosis
Mandrioli, J., D’Amico, R., Zucchi, E., Biasi, S. D., Banchelli, F., Martinelli, I., Simonini, C., Tartaro, D. L., Vicini, R., Fini, N., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-40734-8 · Cited by 84 · see citing works
Causative Genes in Amyotrophic Lateral Sclerosis and Protein Degradation Pathways: a Link to Neurodegeneration
Maurel, C., Dangoumau, A., Marouillat, S., Brulard, C., Chami, A. A., Hergesheimer, R. C., Corcia, P., Blasco, H., Andres, C. R., & Vourc’h, P. (2018) · Molecular Neurobiology · doi:10.1007/s12035-017-0856-0 · Cited by 76 · see citing works
Selective Autophagy Receptors in Neuronal Health and Disease
Conway, O., Akpinar, H. A., Rogov, V. V., & Kirkin, V. (2020) · Journal of Molecular Biology · doi:10.1016/j.jmb.2019.10.013 · Cited by 75 · see citing works
TDP-43 pathology: From noxious assembly to therapeutic removal
Keating, S. S., Gil, R. S., Swanson, M. E. V., Scotter, E. L., & Walker, A. K. (2022) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2022.102229 · Cited by 75 · see citing works
Studying Autophagy in Zebrafish
Mathai, B. J., Meijer, A. H., & Simonsen, A. (2017) · Cells · doi:10.3390/cells6030021 · Cited by 73 · see citing works
“In another study involving the knockdown of p62/sqstm1 in zebrafish, it was seen that the ablation caused a specific locomoter phenotype characterized by a specific axonopathy of descending motor neuron projections [69].”
Background
A perspective on therapies for amyotrophic lateral sclerosis: can disease progression be curbed?
Xu, X., Shen, D., Gao, Y., Zhou, Q., Ni, Y., Meng, H., Shi, H., Le, W., Chen, S., & Chen, S. (2021) · Translational Neurodegeneration · doi:10.1186/s40035-021-00250-5 · Cited by 77 · see citing works
Is amyotrophic lateral sclerosis/frontotemporal dementia an autophagy disease?
Deng, Z., Sheehan, P., Chen, S., & Yue, Z. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0232-6 · Cited by 61 · see citing works
“loss-of-function of p62 in selective autophagy [83, 84].”
Background
DNA Damage and Repair Deficiency in ALS/FTD-Associated Neurodegeneration: From Molecular Mechanisms to Therapeutic Implication
Wang, H., Kodavati, M. M., Britz, G. W., & Hegde, M. L. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.784361 · Cited by 59 · see citing works
“…Xeroderma Pigmentosum, and Trichothiodystrophy, mutations in BER genes associated with ataxia oculomotor apraxia, and DSB repair gene mutations causing ataxia telangiectasia, XLF syndrome, and Ligase 4 syndrome (Le Ber et al., 2003; Kraemer et al., 2007; Chistiakov, 2010; Keimling et al., 2011).”
Background
Multifaceted Genes in Amyotrophic Lateral Sclerosis-Frontotemporal Dementia
Ranganathan, R., Haque, S., Coley, K., Shepheard, S. R., Cooper‐Knock, J., & Kirby, J. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00684 · Cited by 59 · see citing works
Implications of Selective Autophagy Dysfunction for ALS Pathology
Vicencio, E., Beltrán, S., Labrador, L., Manque, P., Nassif, M., & Woehlbier, U. (2020) · Cells · doi:10.3390/cells9020381 · Cited by 58 · see citing works
Pathogenic mutation in the ALS/FTD gene, CCNF, causes elevated Lys48-linked ubiquitylation and defective autophagy
Lee, A., Rayner, S. L., Gwee, S. S. L., Luca, A. D., Shahheydari, H., Sundaramoorthy, V., Ragagnin, A., Morsch, M., Radford, R. A. W., Galper, J., et al. (2017) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-017-2632-8 · Cited by 52 · see citing works
“Defective autophagy has been associated with pathological mutations of several ALS and FTD-linked genes including SOD1 [12], p62/SQSTM1 [13], FUS [14, 15], TARDBP [16], DCTN [17, 18], VCP [19], TBK1 [20, 21], OPTN [22–24], and CHMP2B [25] suggesting that such defects play a causative role in ALS pathogenesis.”
Background
Modeling Environmentally-Induced Motor Neuron Degeneration in Zebrafish
Morrice, J. R., Gregory, C. Y., & Shaw, C. A. (2018) · Scientific Reports · doi:10.1038/s41598-018-23018-w · Cited by 51 · see citing works
Curcumin protects against doxorubicin induced oxidative stress by regulating the Keap1-Nrf2-ARE and autophagy signaling pathways
Liao, D., Shangguan, D., Wu, Y. P., Chen, Y., Liu, N., Tang, J., Yao, D., & Shi, Y. (2023) · Psychopharmacology · doi:10.1007/s00213-023-06357-z · Cited by 46 · see citing works
“In addition, numerous studies have also showed that the activation of autophagy and the p62-Keap1-Nrf2positive feedback loop are protective mechanisms that ameliorate the development of neurodegenerative diseases (Buratta et al. 2020; Lattante et al. 2015).”
Background
Assessing Drug Administration Techniques in Zebrafish Models of Neurological Disease
Chaoul, V., Dib, E., Bedran, J., Khoury, C., Shmoury, O., Harb, F., & Soueid, J. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241914898 · Cited by 45 · see citing works
“demonstrated that the injection of rapamycin into sqstm1 knockdown zebrafish ALS models improved the ALS motor phenotype [280].”
Background
Mammalian target of rapamycin (mTOR) signaling pathway and traumatic brain injury: A novel insight into targeted therapy
Movahedpour, A., Vakili, O., Khalifeh, M., Mousavi, P., Mahmoodzadeh, A., Taheri-Anganeh, M., Razmeh, S., Shabaninejad, Z., Yousefi, F., Behrouj, H., et al. (2022) · Cell Biochemistry and Function · doi:10.1002/cbf.3692 · Cited by 32 · see citing works
Autophagy Dysfunction in ALS: from Transport to Protein Degradation
Cozzi, M., & Ferrari, V. (2022) · Journal of Molecular Neuroscience · doi:10.1007/s12031-022-02029-3 · Cited by 35 · see citing works
“Amelioration of the phenotype was also evidenced upon administration of the autophagy inductor rapamycin, which further supports the hypothesis of a LOF being connected to the P392L substitution (Lattante et al. 2015).”
Background
Potential benefits of medium chain fatty acids in aging and neurodegenerative disease
Dunn, E., Zhang, B., Sahota, V. K., & Augustin, H. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1230467 · Cited by 36 · see citing works
“, 2010), can rescue impaired locomotion in a zebrafish model of ALS (Table 2; Lattante et al., 2015).”
Background
Selective autophagy: the rise of the zebrafish model
Pant, D. C., & Nazarko, T. Y. (2020) · Autophagy · doi:10.1080/15548627.2020.1853382 · Cited by 32 · see citing works
“Abbreviations: AD: Alzheimer disease; ALS: amyotrophic lateral sclerosis; Atg: autophagy-related; CMA: chaperone-mediated autophagy; CQ: chloroquine; HsAMBRA1: human AMBRA1; KD: knockdown; KO: knockout; LD: lipid droplet; MMA: methylmalonic acidemia; PD: Parkinson disease; Tg: transgenic.”
Background
Functional implication of ubiquitinating and deubiquitinating mechanisms in TDP-43 proteinopathies
Tran, N.-N., & Lee, B. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.931968 · Cited by 31 · see citing works
“In addition, rapamycin, which works as an autophagic activator, strongly decreased the pathogenic TDP-43 species and attenuated TDP43-induced neurotoxicity in ALS and FTD models (Cheng et al., 2015; Lattante et al., 2015).”
Background
Therapeutic targeting of ALS pathways: Refocusing an incomplete picture
Maragakis, N. J., de Carvalho, M. A., & Weiss, M. D. (2023) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.51887 · Cited by 31 · see citing works
Efficacy of Ciprofloxacin/Celecoxib combination in zebrafish models of amyotrophic lateral sclerosis
Goldshtein, H., Muhire, A., Légaré, V. P., Pushett, A., Rotkopf, R., Shefner, J. M., Peterson, R. T., Armstrong, G. A. B., & Russek‐Blum, N. (2020) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.51174 · Cited by 30 · see citing works
UXT chaperone prevents proteotoxicity by acting as an autophagy adaptor for p62-dependent aggrephagy
Yoon, M. J., Choi, B.-Y., Kim, E. J., Ohk, J., Yang, C., Choi, Y.-G., Lee, J., Kang, C., Song, H. K., Kim, Y. K., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-22252-7 · Cited by 28 · see citing works
The converging roles of sequestosome-1/p62 in the molecular pathways of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)
Davidson, J. M., Chung, R. S., & Lee, A. (2022) · Neurobiology of Disease · doi:10.1016/j.nbd.2022.105653 · Cited by 26 · see citing works
Myotubularin-related phosphatase 5 is a critical determinant of autophagy in neurons
Chua, J. P., Bedi, K., Paulsen, M. T., Ljungman, M. E., Tank, E. M. H., Kim, E. S., McBride, J. P., Colon, J., Ward, M. E., Weisman, L. S., et al. (2022) · Current Biology · doi:10.1016/j.cub.2022.04.053 · Cited by 25 · see citing works
Endogenous Mechanisms of Neuroprotection: To Boost or Not to Be
Marmolejo-Martínez-Artesero, S., Casas, C., & Romeo-Guitart, D. (2021) · Cells · doi:10.3390/cells10020370 · Cited by 27 · see citing works
Activation of the Nrf2 Pathway as a Therapeutic Strategy for ALS Treatment
Arslanbaeva, L. R., & Bisaglia, M. (2022) · Molecules · doi:10.3390/molecules27051471 · Cited by 27 · see citing works
Poly-GP accumulation due to C9orf72 loss of function induces motor neuron apoptosis through autophagy and mitophagy defects
de Calbiac, H., Renault, S., Haouy, G., Jung, V. A., Roger, K., Zhou, Q., Campanari, M., Chentout, L., Demy, D. L., Marian, A., et al. (2024) · Autophagy · doi:10.1080/15548627.2024.2358736 · Cited by 23 · see citing works
“For this, we used a previously established dose of a specific anti-sqstm1 AMO [42] that by itself does not elicit morphological defects or motor phenotypes in zebrafish larvae, as shown in Fig.”
InfluentialSelf-citation
In a search for efficient treatment for amyotrophic lateral sclerosis: Old drugs for new approaches
Kukharsky, M. S., Skvortsova, V. I., Бачурин, С. О., & Buchman, V. L. (2020) · Medicinal Research Reviews · doi:10.1002/med.21725 · Cited by 21 · see citing works
Molecular Insights into Aggrephagy: Their Cellular Functions in the Context of Neurodegenerative Diseases
Cóppola-Segovia, V., & Reggiori, F. (2024) · Journal of Molecular Biology · doi:10.1016/j.jmb.2024.168493 · Cited by 18 · see citing works
The role of autophagy in the pathogenesis and treatment of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)
Beckers, J., & Damme, P. V. (2025) · Autophagy Reports · doi:10.1080/27694127.2025.2474796 · Cited by 16 · see citing works
Genetic architecture of amyotrophic lateral sclerosis: a comprehensive review
Yuan, L., Yang, Y., Guo, Y., & Deng, H. (2025) · Journal of genetics and genomics/Journal of Genetics and Genomics · doi:10.1016/j.jgg.2025.05.008 · Cited by 15 · see citing works
Axonopathy Underlying Amyotrophic Lateral Sclerosis: Unraveling Complex Pathways and Therapeutic Insights
Luan, T., Li, Q., Huang, Z., Feng, Y., Xu, D., Zhou, Y., Hu, Y., & Wang, T. (2024) · Neuroscience Bulletin · doi:10.1007/s12264-024-01267-2 · Cited by 14 · see citing works
“…of leads to motor neuron axon shortening and swimming deficits, which can be rescued by treatment with rapamycin, an autophagy activator, or overexpression of wild-type but not mutant SQSTM1 [180], suggesting that the SQSTM1-related autophagy pathway may contribute to the axonopathy underlying ALS.”
Review: Modelling the pathology and behaviour of frontotemporal dementia
Solomon, D. A., Mitchell, J. C., Salcher-Konrad, M.-T., Vance, C. A., & Mizielinska, S. (2018) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12536 · Cited by 14 · see citing works
Tumor-associated macrophages enhance peripheral nerve tumor infiltration and spinal cord repair
Dolci, S., Mannino, L., Rossi, E., Bottani, E., Ciarpella, F., Piazza, N., Karkossa, I., Chio, M. D., Savino, B., Lucidi, B., et al. (2026) · Immunity · doi:10.1016/j.immuni.2025.12.016 · Cited by 12 · see citing works
Multifaceted role of SMCR8 as autophagy regulator
Jung, J., & Behrends, C. (2017) · Small GTPases · doi:10.1080/21541248.2017.1346553 · Cited by 12 · see citing works
“In zebrafish C9ORF72 knockdown induced a motor deficiency, whereas C9ORF72 knockout mice displayed immunological phenotypes and a shortened life-span but no overt neurodegeneration occurred.15,19,54,55,75-77 However, lack of C9ORF72 or SMCR8 impaired clearance of p62-positive aggregates and resulted in reduced surviva…”
Background
Hcfc1a regulates neural precursor proliferation and asxl1 expression in the developing brain
Castro, V. L., Reyes, J. F., Reyes‐Nava, N. G., Paz, D., & Quintana, A. M. (2020) · BMC Neuroscience · doi:10.1186/s12868-020-00577-1 · Cited by 11 · see citing works
Zebrafish Models of Autosomal Recessive Ataxias
Quelle‐Regaldie, A., Sobrido‐Cameán, D., Barreiro‐Iglesias, A., Sobrido, M. J., & Sanchez, L. E. (2021) · Cells · doi:10.3390/cells10040836 · Cited by 11 · see citing works
Targeting mitochondrial Ca2+ uptake for the treatment of amyotrophic lateral sclerosis
Zhong, R., Rua, M. T., & Wei‐LaPierre, L. (2023) · The Journal of Physiology · doi:10.1113/jp284143 · Cited by 10 · see citing works
“Knockdown of SQSTM1/p62 in zebrafish induced an ALS/FTD-like phenotype (Lattante et al., 2014).”
Background
Functional Characterization of Neurofilament Light Splicing and Misbalance in Zebrafish
Demy, D. L., Campanari, M., Munoz‐Ruiz, R., Durham, H. D., Gentil, B. J., & Kabashi, E. (2020) · Cells · doi:10.3390/cells9051238 · Cited by 10 · see citing works
Self-citation
Development of a high-throughput tailored imaging method in zebrafish to understand and treat neuromuscular diseases
Lescouzères, L., Bordignon, B., & Bomont, P. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.956582 · Cited by 10 · see citing works
Molecular targets and approaches to restore autophagy and lysosomal capacity in neurodegenerative disorders
Bastien, J., Menon, S., Messa, M., & Nyfeler, B. (2021) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2021.101018 · Cited by 9 · see citing works
Role of Autophagy and Mitophagy in Neurodegenerative Disorders
Kapil, L., Kumar, V., Kaur, S., Sharma, D., Singh, C., & Singh, A. (2023) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527322666230327092855 · Cited by 8 · see citing works
Diving deep: zebrafish models in motor neuron degeneration research
Garg, V., & Geurten, B. R. H. (2024) · Frontiers in Neuroscience · doi:10.3389/fnins.2024.1424025 · Cited by 8 · see citing works
UXT at the crossroads of cell death, immunity and neurodegenerative diseases
Han, P., Mo, S., Wang, Z., Xu, J., Fu, X., & Tian, Y. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1179947 · Cited by 7 · see citing works
Motoneuron Disease: Basic Science
Ilieva, H. S., & Maragakis, N. J. (2017) · Advances in neurobiology · doi:10.1007/978-3-319-57193-5_6 · Cited by 6 · see citing works
First report of novel mutation (c.790del) on SQSTM1 gene on a family with childhood onset of progressive cerebellar ataxia with vertical gaze palsy
Jalali, H., Khoshaeen, A., Mahdavi, M. R., & Mahdavi, M. (2022) · Clinical Case Reports · doi:10.1002/ccr3.6203 · Cited by 6 · see citing works
Sephin1 reduces TDP-43 cytoplasmic mislocalization and improves motor neuron survival in ALS models
Abgueguen, E., Tortarolo, M., Rouvière, L., Marcuzzo, S., Camporeale, L., Henriques, A., Pasetto, L., Culley, G. R., Bonetto, V., Marian, A., et al. (2025) · Life Science Alliance · doi:10.26508/lsa.202403195 · Cited by 5 · see citing works
“Locomotor phenotypes of 50 hpf zebra ﬁ sh embryos were assessed using the Touched-Evoked Escape Response (TEER) test, as previously described (Ciura et al, 2013; Lattante et al, 2015; de Calbiac et al, 2018).”
Self-citation
Intrinsically accelerated cellular degradation is amplified by TDP-43 loss in ALS-vulnerable motor neurons in a zebrafish model
Asakawa, K., Tomita, T., Shioya, S., Handa, H., Saeki, Y., & Kawakami, K. (2025) · Nature Communications · doi:10.1038/s41467-025-65097-0 · Cited by 6 · see citing works
Roflupram alleviates autophagy defects and reduces mutant hSOD1-induced motor neuron damage in cell and mouse models of amyotrophic lateral sclerosis
Huo, D., Liang, W., Wang, D., Liu, Q., Wang, H., Wang, Y., Zhang, C., Cong, C., Su, X., Tan, X., et al. (2024) · Neuropharmacology · doi:10.1016/j.neuropharm.2023.109812 · Cited by 5 · see citing works
mTOR, Autophagy, Aminoacidopathies, and Human Genetic Disorders
Ainslie, G. R., Gibson, K. M., & Vogel, K. R. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-802733-2.00010-4 · Cited by 4 · see citing works
Autophagy in Drosophila and Zebrafish
Duan, X., & Tong, C. (2021) · Advances in experimental medicine and biology · doi:10.1007/978-981-16-2830-6_15 · Cited by 3 · see citing works
The Importance of Olfactory and Motor Endpoints for Zebrafish Models of Neurodegenerative Disease
Shamchuk, A. L., & Tierney, K. B. (2013) · Elsevier eBooks · doi:10.1016/b978-0-12-415894-8.00027-0 · Cited by 2 · see citing works
The Importance of Olfactory and Motor Endpoints for Zebrafish Models of Neurodegenerative Disease
Shamchuk, A. L., Allison, W. T., & Tierney, K. B. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-809468-6.00021-8 · Cited by 2 · see citing works
Multifaceted Genes in Amyotrophic Lateral Sclerosis-Frontotemporal Dementia
(2021) · Frontiers research topics · doi:10.3389/978-2-88966-904-2 · Cited by 3 · see citing works
Tumor-associated macrophages enhance tumor innervation and spinal cord repairPreprint
Dolci, S., Mannino, L., Campanelli, A., Rossi, E., Bottani, E., Ciarpella, F., Karkossa, I., Setten, E., Savino, B., Pruonto, G., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.12.19.629374 · Cited by 2 · see citing works
Mutant SQSTM1/p62 Signaling in Paget’s Disease of Bone
Rea, S. L., & Layfield, R. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-805083-5.00005-1
Integrative Analysis of Drug-Gene Expression Signatures in Human Pluripotent Stem Cells Identifies Novel Drug Candidates for ALS and Monogenic DiseasesPreprint
Roussange, F., Gide, J., Tournois, J., Cailleret, M., Boland, A., Battail, C., Deleuze, J., Polvèche, H., Auboeuf, D., Brockmann, K., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.02.04.636445
Self-citation
Intrinsic and TDP-43 dysfunction-induced catabolic stress elicit neuroprotective cellular degradation in ALS-vulnerable motor neuronsPreprint
Asakawa, K., Tomita, T., Shioya, S., Handa, H., Saeki, Y., & Kawakami, K. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.05.06.652552
EIPR1 variants cause a neurodevelopmental disorder with endolysosomal and dense core vesicle defects
Ghosh, S., Singh, J., Damseh, N. S., Severino, M., Pace, R. D., Golding, A. E., Jarník, M., Thakran, P., Faivre, L. O., Heitz, J., et al. (2025) · Brain · doi:10.1093/brain/awaf371
Dynactin1 mutations associated with amyotrophic lateral sclerosis and their effect on axonal transport and neuromuscular junction formation
Bercier, V. (2017) · doi:10.70675/97958154z085az46f7z984fz7595cc2bf079
Génétique de la Sclérose Latérale Amyotrophique et rôle de la voie de SUMOylation dans l'agrégation de la protéine TDP-43
Maurel, C. (2018) · theses.fr (ABES) · doi:10.70675/06af88a8z908cz41aaz9b6dz8cbea6bde2a8
Mechanisms of C9ORF72 pathogenicity and related autophagy impairment in amyotrophic lateral sclerosis
de Calbiac, H. (2019) · theses.fr (ABES) · doi:10.70675/bafe951fz8332z4b0azb55bzac8a4af1955b
Study of neuromuscular diseases in zebrafish : from pathophysiological mechanisms towards new therapies for Giant Axonal Neuropathy
Lescouzères, L. (2022) · doi:10.70675/7575bf2az4f2dz4e2az9468z4da991a74ade
Propagation et toxicité de la superoxide dismutase 1 dans la Sclérose Latérale Amyotrophique modélisée par des neurones moteurs dérivés de cellules souches pluripotentes induites
Jost-Mousseau, C. (2024) · theses.fr (ABES) · doi:10.70675/c6d262f3zda3ez4005z96ffzb15b50db412b
Integrative analysis of drug-gene signatures in human pluripotent stem cells reveals prazosin as a novel SQSTM1 regulator for ALS therapeutics
Roussange, F., Gide, J., Tournois, J., Cailleret, M., Boland, A., Battail, C., Deleuze, J., Polvèche, H., Auboeuf, D., Brockmann, K., et al. (2026) · Stem Cell Reports · doi:10.1016/j.stemcr.2026.102977
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Clinical significance of SQSTM1 variants in ALS: report of p.Arg119Cys and literature review
Su, B., Li, L., Zheng, X., Ma, H., Li, X., & Feng, X. (2026) · Neurogenetics · doi:10.1007/s10048-026-00924-0
“In the zebrafish model with SQSTM1 knock-down, rapamycin treatment improved the motor phenotype, suggesting that the regulation of the mTOR pathway may have therapeutic significance for SQSTM1 -related ALS [46].”
Emerging therapeutic approaches in amyotrophic lateral sclerosis: From gene therapy and stem cells to autophagy and nanotechnology
Chowdhury, S., Kar, K., Chakraborty, P., Kuilya, M., Prajapati, B. G., Ankul Singh, S., & Sridevi, S. (2026) · Current Proteomics · doi:10.1016/j.curpro.2026.100151

The role of SQSTM1/P62 in axonal development and degeneration in an ALS-FTLD context
Young, M. J. (2020) · Nottingham ePrints (University of Nottingham)
SQSTM1 mutations in frontotemporal lobar degeneration and amyotrophic lateral sclerosis
Rubino, E., Rainero, I., Chiò, A., Rogaeva, E., Galimberti, D., Fenoglio, P., Grinberg, Y., Isaia, G., Calvo, A., Gentile, S., et al. (2012) · Neurology · doi:10.1212/wnl.0b013e31826e25df · Cited by 286 · see citing works
Functional links between SQSTM1 and ALS2 in the pathogenesis of ALS: cumulative impact on the protection against mutant SOD1-mediated motor dysfunction in mice
Hadano, S., Mitsui, S., Pan, L., Otomo, A., Kubo, M., Sato, K., Ono, S., Onodera, W., Abe, K., Chen, X.-P., et al. (2016) · Human Molecular Genetics · doi:10.1093/hmg/ddw180 · Cited by 60 · see citing works
Defective recognition of LC3B by mutant SQSTM1/p62 implicates impairment of autophagy as a pathogenic mechanism in ALS-FTLD
Goode, A., Butler, K., Long, J., Cavey, J., Scott, D., Shaw, B., Sollenberger, J., Gell, C., Johansen, T., Oldham, N. J., et al. (2016) · Autophagy · doi:10.1080/15548627.2016.1170257 · Cited by 153 · see citing works
SQSTM1, a protective factor of SOD1-linked motor neuron disease, regulates the accumulation and distribution of ubiquitinated protein aggregates in neuron
Mitsui, S., Otomo, A., Sato, K., Ishiyama, M., Shimakura, K., Okada-Yamaguchi, C., Warabi, E., Yanagawa, T., Aoki, M., Shang, H., et al. (2022) · Neurochemistry International · doi:10.1016/j.neuint.2022.105364 · Cited by 8 · see citing works

Authors: Lattante, S., de Calbiac, H., Le Ber, I., Brice, A., Ciura, S., & Kabashi, E.
Affiliations: Centre National de la Recherche Scientifique (FR)
Corresponding author: Ciura, Sorana
Kabashi, Edor
ORCID: Lattante, Serena
Brice, Alexis
Ciura, Sorana
Kabashi, Edor
Venue: Human Molecular Genetics
Publisher: Oxford University Press (OUP)
Published: 2014-11-19
Volume: 24
Issue: 6
Pages: 1682-1690
ISSN: 0964-6906 (ISSN-L)
1460-2083
DOI: 10.1093/hmg/ddu580
OpenAlex: W2155383466
Cited by: 90
References: 55
Citations by year: 2026: 4 · 2025: 7 · 2024: 8 · 2023: 8 · 2022: 12 · 2021: 10 · 2020: 9 · 2019: 4 · 2018: 6 · 2017: 11 · 2016: 6 · 2015: 4 · 2013: 1
FWCI: 4.56
Type: journal article
Language: en
Open access: closed
Locations: Human Molecular Genetics (publishedVersion)
PubMed (publishedVersion)
AIRUS (submittedVersion)
Funders: Agence Nationale de la Recherche (ANR-10-IAIHU06, 10-IAIHU-06, ANR-10)
Institut National de la Santé et de la Recherche Médicale (ANR-10-IAIHU-06)
Fondation pour la Recherche Médicale (PLP20141031462, ANR-10-IAIHU-06)
Association pour la Recherche sur la Sclérose Latérale Amyotrophique et autres Maladies du Motoneurone (ANR-10-IAIHU-06)
Topics: Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
Keywords: p62, amyotrophic lateral sclerosis, frontotemporal lobar degeneration, zebrafish model, locomotor deficits, rapamycin, mTOR signaling, autophagy, splicing mutation, loss-of-function phenotypes, neurodegeneration
MeSH terms: Sequestosome-1 Protein, Amyotrophic Lateral Sclerosis, Animals, Disease Models, Animal, Locomotion, Phenotype, Zebrafish, Sirolimus, Zebrafish Proteins, Adaptor Proteins, Signal Transducing, Gene Knockdown Techniques, Frontotemporal Lobar Degeneration, TOR Serine-Threonine Kinases

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Sqstm1 knock-down causes a locomotor phenotype ameliorated by rapamycin in a zebrafish model of ALS/FTLD

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