Sporadic ALS hiPSC-derived motor neurons show axonal defects linked to altered axon guidance pathways
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the selective and progressive loss of motor neurons, leading to gradual paralysis and death within 2 to 5 years after diagnosis. The exact underlying pathogenic mechanism(s) remain elusive. This is parti...
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| Language: | English |
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Elsevier
2025-03-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996125000312 |
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| author | Lisha Ye Katarina Stoklund Dittlau Adria Sicart Rekin'’s Janky Philip Van Damme Ludo Van Den Bosch |
| author_facet | Lisha Ye Katarina Stoklund Dittlau Adria Sicart Rekin'’s Janky Philip Van Damme Ludo Van Den Bosch |
| author_sort | Lisha Ye |
| collection | DOAJ |
| description | Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the selective and progressive loss of motor neurons, leading to gradual paralysis and death within 2 to 5 years after diagnosis. The exact underlying pathogenic mechanism(s) remain elusive. This is particularly the case for sporadic ALS (sALS), representing 90 % of cases, as modelling a sporadic disease is extremely difficult. We used human induced pluripotent stem cell (hiPSC)-derived motor neurons from sALS patients to investigate early disease mechanisms. The earliest phenotype that we observed were profound axonal defects including impaired axonal transport, defective axonal outgrowth and a reduced formation of neuromuscular junctions. Transcriptomic profiling revealed significant dysregulation in axon guidance pathways, with upregulation of specific axonal regeneration-inhibiting genes, such as EphA4 and DCC in sALS motor neurons. Our findings suggest that dysregulation of axon guidance pathways contributes to axonal defects and that this could play a crucial role in the pathogenesis of sALS. |
| format | Article |
| id | doaj-art-306da3beeb8e4940b01446813ed9199f |
| institution | Kabale University |
| issn | 1095-953X |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj-art-306da3beeb8e4940b01446813ed9199f2025-02-05T04:31:08ZengElsevierNeurobiology of Disease1095-953X2025-03-01206106815Sporadic ALS hiPSC-derived motor neurons show axonal defects linked to altered axon guidance pathwaysLisha Ye0Katarina Stoklund Dittlau1Adria Sicart2Rekin'’s Janky3Philip Van Damme4Ludo Van Den Bosch5KU Leuven - University of Leuven, Department of Neurosciences and Leuven Brain Institute (LBI), Leuven, Belgium; Laboratory of Neurobiology, VIB Center for Brain & Disease Research, Leuven, BelgiumKU Leuven - University of Leuven, Department of Neurosciences and Leuven Brain Institute (LBI), Leuven, Belgium; Laboratory of Neurobiology, VIB Center for Brain & Disease Research, Leuven, BelgiumKU Leuven - University of Leuven, Department of Neurosciences and Leuven Brain Institute (LBI), Leuven, Belgium; Laboratory of Neurobiology, VIB Center for Brain & Disease Research, Leuven, BelgiumVIB Nucleomics Core, Leuven, BelgiumKU Leuven - University of Leuven, Department of Neurosciences and Leuven Brain Institute (LBI), Leuven, Belgium; Laboratory of Neurobiology, VIB Center for Brain & Disease Research, Leuven, Belgium; University Hospitals Leuven, Department of Neurology, Leuven, BelgiumKU Leuven - University of Leuven, Department of Neurosciences and Leuven Brain Institute (LBI), Leuven, Belgium; Laboratory of Neurobiology, VIB Center for Brain & Disease Research, Leuven, Belgium; Corresponding author at: KU Leuven - University of Leuven, Department of Neurosciences and Leuven Brain Institute (LBI), Leuven, Belgium.Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the selective and progressive loss of motor neurons, leading to gradual paralysis and death within 2 to 5 years after diagnosis. The exact underlying pathogenic mechanism(s) remain elusive. This is particularly the case for sporadic ALS (sALS), representing 90 % of cases, as modelling a sporadic disease is extremely difficult. We used human induced pluripotent stem cell (hiPSC)-derived motor neurons from sALS patients to investigate early disease mechanisms. The earliest phenotype that we observed were profound axonal defects including impaired axonal transport, defective axonal outgrowth and a reduced formation of neuromuscular junctions. Transcriptomic profiling revealed significant dysregulation in axon guidance pathways, with upregulation of specific axonal regeneration-inhibiting genes, such as EphA4 and DCC in sALS motor neurons. Our findings suggest that dysregulation of axon guidance pathways contributes to axonal defects and that this could play a crucial role in the pathogenesis of sALS.http://www.sciencedirect.com/science/article/pii/S0969996125000312Amyotrophic lateral sclerosis (ALS)Sporadic ALSHuman induced pluripotent stem cells (hiPSCs)Axonal transportAxonal outgrowthNeuromuscular junctions |
| spellingShingle | Lisha Ye Katarina Stoklund Dittlau Adria Sicart Rekin'’s Janky Philip Van Damme Ludo Van Den Bosch Sporadic ALS hiPSC-derived motor neurons show axonal defects linked to altered axon guidance pathways Neurobiology of Disease Amyotrophic lateral sclerosis (ALS) Sporadic ALS Human induced pluripotent stem cells (hiPSCs) Axonal transport Axonal outgrowth Neuromuscular junctions |
| title | Sporadic ALS hiPSC-derived motor neurons show axonal defects linked to altered axon guidance pathways |
| title_full | Sporadic ALS hiPSC-derived motor neurons show axonal defects linked to altered axon guidance pathways |
| title_fullStr | Sporadic ALS hiPSC-derived motor neurons show axonal defects linked to altered axon guidance pathways |
| title_full_unstemmed | Sporadic ALS hiPSC-derived motor neurons show axonal defects linked to altered axon guidance pathways |
| title_short | Sporadic ALS hiPSC-derived motor neurons show axonal defects linked to altered axon guidance pathways |
| title_sort | sporadic als hipsc derived motor neurons show axonal defects linked to altered axon guidance pathways |
| topic | Amyotrophic lateral sclerosis (ALS) Sporadic ALS Human induced pluripotent stem cells (hiPSCs) Axonal transport Axonal outgrowth Neuromuscular junctions |
| url | http://www.sciencedirect.com/science/article/pii/S0969996125000312 |
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