ArticleCell stem cell2023
SYF2 suppression mitigates neurodegeneration in models of diverse forms of ALS.
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Article in Cell stem cell, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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13citing papers in PubMed
5.3field-weighted citation impact, top 4% of its field
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Who cites it
13 citing papers in PubMed, 26 citations in OpenAlex.
- Single-cell sequencing and machine learning-based prediction of spliceosome-associated factor 2 may represent potential targets for osteoarthritis.Osteoarthritis and cartilage open · 2026Article
- The Ku80-p53-SIRT1 axis in DNA damage response contributes to sporadic and familial ALS and FTD.Nature communications · 2025Article
- Antisense oligonucleotide depletion ofmedRxiv : the preprint server for health sciences · 2025Article
- Roll-to-Roll (R2R) High-Throughput Manufacturing of Foil-Based Microfluidic Chips for Neurite Outgrowth Studies.Micromachines · 2025Article
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- C9ORF72 poly-PR disrupts expression of ALS/FTD-implicated STMN2 through SRSF7.Acta neuropathologica communications · 2025Article
- Investigation of early axonal phenotypes in an iPSC-derived ALS cellular model using a microfluidic device.Frontiers in cellular neuroscience · 2025Article
- Aberrant protein aggregation in amyotrophic lateral sclerosis.Journal of neurology · 2024Review
- Antisense Oligonucleotides (ASOs) in Motor Neuron Diseases: A Road to Cure in Light and Shade.International journal of molecular sciences · 2024Review
- Drug Screening and Validation Targeting TDP-43 Proteinopathy for Amyotrophic Lateral Sclerosis.Aging and disease · 2024Review
- In Vitro Models of Amyotrophic Lateral Sclerosis.Cellular and molecular neurobiology · 2023Review
- iPSC motor neurons, but not other derived cell types, capture gene expression changes in postmortem sporadic ALS motor neurons.Cell reports · 2023Article
- CRISPR interference to evaluate modifiers ofFrontiers in cell and developmental biology · 2023Article
Corrections and comments
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Authors and funding
28 authors at 5 institutions in 1 country.
Gabriel R LinaresDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Los Angeles, CA 90033, USA; Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA.
Yichen LiDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Los Angeles, CA 90033, USA; Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA.
Wen-Hsuan ChangAcuraStem Incorporated, Monrovia, CA 91016, USA.
Jasper Rubin-SiglerDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Los Angeles, CA 90033, USA; Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA.
Stacee MendoncaAcuraStem Incorporated, Monrovia, CA 91016, USA.
Sarah HongAcuraStem Incorporated, Monrovia, CA 91016, USA.
Yunsun EohDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Los Angeles, CA 90033, USA; Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA.
Wenxuan GuoDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Los Angeles, CA 90033, USA; Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA.
Yi-Hsuan HuangDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Los Angeles, CA 90033, USA; Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA.
Jonathan ChangDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Los Angeles, CA 90033, USA; Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA.
Sharon TuDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Los Angeles, CA 90033, USA; Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA.
Nomongo DorjsurenDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Los Angeles, CA 90033, USA; Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA.
Manuel SantanaDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Los Angeles, CA 90033, USA; Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA.
Shu-Ting HungDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Los Angeles, CA 90033, USA; Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA.
Johnny YuDepartment of Biochemistry and Biophysics, University of California, San Francisco, CA 94158, USA; Department of Urology, University of California, San Francisco, CA 94158, USA; Bakar Computational Health Sciences Institute, University of California, San Francisco, CA 94158, USA.
Joscany PerezDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Los Angeles, CA 90033, USA; Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA.
Michael ChickeringDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Los Angeles, CA 90033, USA; Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA.
Tze-Yuan ChengSVision LLC, Bellevue, WA 98006, USA.
Chi-Chou HuangSVision LLC, Bellevue, WA 98006, USA.
Shih-Jong James LeeSVision LLC, Bellevue, WA 98006, USA.
Hao-Jen DengDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Los Angeles, CA 90033, USA; Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA.
Kieu-Tram BachDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Los Angeles, CA 90033, USA; Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA.
Kamden GrayDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Los Angeles, CA 90033, USA; Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA.
Vishvak SubramanyamDepartment of Biochemistry and Biophysics, University of California, San Francisco, CA 94158, USA; Department of Urology, University of California, San Francisco, CA 94158, USA; Bakar Computational Health Sciences Institute, University of California, San Francisco, CA 94158, USA.
Jeffrey RosenfeldDepartment of Neurology, Loma Linda University, Loma Linda, CA 92350, USA.
Samuel V AlworthAcuraStem Incorporated, Monrovia, CA 91016, USA.
Hani GoodarziDepartment of Biochemistry and Biophysics, University of California, San Francisco, CA 94158, USA; Department of Urology, University of California, San Francisco, CA 94158, USA; Bakar Computational Health Sciences Institute, University of California, San Francisco, CA 94158, USA.
Justin K IchidaDepartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Los Angeles, CA 90033, USA; Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA. Electronic address: ichida@usc.edu.
University of Southern California · USBroad Center · USBellevue Hospital Center · USUniversity of California, San Francisco · USLoma Linda University · US
Funding
Validating Secretory Autophagy as a Therapeutic Strategy for Diverse Forms of ALS and FTDR01NS097850 · NINDS · UNIVERSITY OF SOUTHERN CALIFORNIA · PI ICHIDA, JUSTIN KAWIKA · 2016 to 2024
$5.5MLeveraging Natural Phenotypic Variations of Heterogenous ALS Populations-in-a-Dish to Enable Scalable Drug DiscoveryR01NS131409 · NINDS · UNIVERSITY OF SOUTHERN CALIFORNIA · PI GOODARZI, HANI, ICHIDA, JUSTIN KAWIKA · 2022 to 2025
$4.9MNHGRI Genome Sequencing Program Coordinating CenterU24HG008956 · NHGRI · RUTGERS, THE STATE UNIV OF N.J. · PI BUYSKE, STEVEN G, MATISE, TARA C. · 2016 to 2020
$4.9MKinetic Phenotype Discovery Informatics for Neurological DiseasesR44NS097094 · NINDS · SVISION, LLC. · PI LEE, SHIH-JONG J · 2016 to 2019
$3.0MLineage reprogramming for hearing loss: development of drug screening and gene therapy approachesR01DC015530 · NIDCD · UNIVERSITY OF SOUTHERN CALIFORNIA · PI ICHIDA, JUSTIN KAWIKA, MCMAHON, ANDREW P. · 2016 to 2020
$3.0MTraining in Developmental Biology, Stem Cells and RegenerationT32HD060549 · NICHD · UNIVERSITY OF SOUTHERN CALIFORNIA · PI Gage D Crump · 2011 to 2026
$2.5MConversion of Fibroblasts to fxnal Spinal Motor Neurons Using Defined FactorR00NS077435 · NINDS · UNIVERSITY OF SOUTHERN CALIFORNIA · PI ICHIDA, JUSTIN KAWIKA · 2013 to 2015
$737kHiSeq X SequencerS10OD021553 · OD · UNIVERSITY OF WASHINGTON · PI NICKERSON, DEBORAH A · 2016 to 2016
$600kConversion of fibroblasts to functional spinal motor neurons using defined factorK99NS077435 · NINDS · HARVARD UNIVERSITY · PI ICHIDA, JUSTIN KAWIKA · 2011 to 2012
$177kNHGRI NIH HHS U24 HG008956NICHD NIH HHS T32 HD060549NIDCD NIH HHS R01 DC015530NIH HHS S10 OD021553NINDS NIH HHS K99 NS077435NINDS NIH HHS R00 NS077435NINDS NIH HHS R01 NS097850NINDS NIH HHS R01 NS131409NINDS NIH HHS R44 NS097094
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by many diverse genetic etiologies. Although therapeutics that specifically target causal mutations may rescue individual types of ALS, such approaches cannot treat most patients since they have unknown genetic etiology. Thus, there is a critical need for therapeutic strategies that rescue multiple forms of ALS. Here, we combine phenotypic chemical screening on a diverse cohort of ALS patient-derived neurons with bioinformatic analysis of large chemical and genetic perturbational datasets to identify broadly effective genetic targets for ALS. We show that suppressing the gene-encoding, spliceosome-associated factor SYF2 alleviates TDP-43 aggregation and mislocalization, improves TDP-43 activity, and rescues C9ORF72 and causes sporadic ALS neuron survival. Moreover, Syf2 suppression ameliorates neurodegeneration, neuromuscular junction loss, and motor dysfunction in TDP-43 mice. Thus, suppression of spliceosome-associated factors such as SYF2 may be a broadly effective therapeutic approach for ALS.
Indexed as
Amyotrophic Lateral SclerosisNeurodegenerative DiseasesAnimalsDNA-Binding ProteinsMiceMotor NeuronsMutationDNA-Binding Proteinsamyotrophic lateral sclerosisandrogensconnectivity mapdrug screeninduced pluripotent stem cellsnineteen complexnorgestrelspliceosomeSYF2TDP-43
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