Astrocyte‐targeting RNA interference against mutated superoxide dismutase 1 induces motoneuron plasticity and protects fast‐fatigable motor units in a mouse model of amyotrophic lateral sclerosis
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| Titel: | Astrocyte‐targeting RNA interference against mutated superoxide dismutase 1 induces motoneuron plasticity and protects fast‐fatigable motor units in a mouse model of amyotrophic lateral sclerosis |
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| Autoren: | Rochat, Cylia, Bernard‐marissal, Nathalie, Källstig, Emma, Pradervand, Sylvain, Perrin, Florence, Aebischer, Patrick, Raoul, Cédric, Schneider, Bernard |
| Weitere Verfasser: | Raoul, Cédric, Dou Goarin, Carine |
| Quelle: | Glia Glia, vol. 70, no. 5, pp. 842-857 |
| Verlagsinformationen: | Wiley, 2022. |
| Publikationsjahr: | 2022 |
| Schlagwörter: | Motor Neurons, 0301 basic medicine, amyotrophic lateral sclerosis, Amyotrophic Lateral Sclerosis/genetics, Amyotrophic Lateral Sclerosis/metabolism, Amyotrophic Lateral Sclerosis/therapy, Animals, Astrocytes/metabolism, Disease Models, Animal, Mice, Mice, Transgenic, Motor Neurons/metabolism, RNA Interference, Superoxide Dismutase/genetics, Superoxide Dismutase/metabolism, Superoxide Dismutase-1/genetics, Superoxide Dismutase-1/metabolism, RNA interference, astrocyte, gene therapy, neuromuscular function, neuronal plasticity, superoxide dismutase 1, Superoxide Dismutase, Amyotrophic Lateral Sclerosis, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV] Life Sciences [q-bio], 03 medical and health sciences, Superoxide Dismutase-1, Astrocytes, Research Articles |
| Beschreibung: | In amyotrophic lateral sclerosis (ALS) caused by SOD1 gene mutations, both cell‐autonomous and noncell‐autonomous mechanisms lead to the selective degeneration of motoneurons (MN). Here, we evaluate the therapeutic potential of gene therapy targeting mutated SOD1 in mature astrocytes using mice expressing the mutated SOD1G93A protein. An AAV‐gfaABC1D vector encoding an artificial microRNA is used to deliver RNA interference against mutated SOD1 selectively in astrocytes. The treatment leads to the progressive rescue of neuromuscular junction occupancy, to the recovery of the compound muscle action potential in the gastrocnemius muscle, and significantly improves neuromuscular function. In the spinal cord, gene therapy targeting astrocytes protects a small pool of the most vulnerable fast‐fatigable MN until disease end stage. In the gastrocnemius muscle of the treated SOD1G93A mice, the fast‐twitch type IIB muscle fibers are preserved from atrophy. Axon collateral sprouting is observed together with muscle fiber type grouping indicative of denervation/reinnervation events. The transcriptome profiling of spinal cord MN shows changes in the expression levels of factors regulating the dynamics of microtubules. Gene therapy delivering RNA interference against mutated SOD1 in astrocytes protects fast‐fatigable motor units and thereby improves neuromuscular function in ALS mice. |
| Publikationsart: | Article Other literature type |
| Dateibeschreibung: | application/pdf |
| Sprache: | English |
| ISSN: | 1098-1136 0894-1491 |
| DOI: | 10.1002/glia.24140 |
| Zugangs-URL: | https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/glia.24140 https://pubmed.ncbi.nlm.nih.gov/34978340 https://hal.science/hal-04767189v1/document https://doi.org/10.1002/glia.24140 https://hal.science/hal-04767189v1 https://hal.science/hal-03511644v1/document https://hal.science/hal-03511644v1 https://doi.org/10.1002/glia.24140 https://serval.unil.ch/notice/serval:BIB_0DDA52E3E962 http://nbn-resolving.org/urn/resolver.pl?urn=urn:nbn:ch:serval-BIB_0DDA52E3E9622 https://serval.unil.ch/resource/serval:BIB_0DDA52E3E962.P001/REF.pdf |
| Rights: | CC BY NC |
| Dokumentencode: | edsair.doi.dedup.....20e1f9283d784fb6dcafc113711daf4f |
| Datenbank: | OpenAIRE |
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Nájsť tento článok vo Web of Science | Abstract: | In amyotrophic lateral sclerosis (ALS) caused by SOD1 gene mutations, both cell‐autonomous and noncell‐autonomous mechanisms lead to the selective degeneration of motoneurons (MN). Here, we evaluate the therapeutic potential of gene therapy targeting mutated SOD1 in mature astrocytes using mice expressing the mutated SOD1G93A protein. An AAV‐gfaABC1D vector encoding an artificial microRNA is used to deliver RNA interference against mutated SOD1 selectively in astrocytes. The treatment leads to the progressive rescue of neuromuscular junction occupancy, to the recovery of the compound muscle action potential in the gastrocnemius muscle, and significantly improves neuromuscular function. In the spinal cord, gene therapy targeting astrocytes protects a small pool of the most vulnerable fast‐fatigable MN until disease end stage. In the gastrocnemius muscle of the treated SOD1G93A mice, the fast‐twitch type IIB muscle fibers are preserved from atrophy. Axon collateral sprouting is observed together with muscle fiber type grouping indicative of denervation/reinnervation events. The transcriptome profiling of spinal cord MN shows changes in the expression levels of factors regulating the dynamics of microtubules. Gene therapy delivering RNA interference against mutated SOD1 in astrocytes protects fast‐fatigable motor units and thereby improves neuromuscular function in ALS mice. |
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| ISSN: | 10981136 08941491 |
| DOI: | 10.1002/glia.24140 |