Subpial delivery of adeno-associated virus 9-synapsin-caveolin-1 (AAV9-SynCav1) preserves motor neuron and neuromuscular junction morphology, motor function, delays disease onset, and extends survival in hSOD1G93A mice
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| Názov: | Subpial delivery of adeno-associated virus 9-synapsin-caveolin-1 (AAV9-SynCav1) preserves motor neuron and neuromuscular junction morphology, motor function, delays disease onset, and extends survival in hSOD1G93A mice |
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| Autori: | Wang, Shanshan, Ichinomiya, Taiga, Savchenko, Paul, Wang, Dongsheng, Sawada, Atsushi, Li, Xiaojing, Duong, Tiffany, Li, Wenxi, Bonds, Jacqueline A, Kim, Eun Jung, Miyanohara, Atsushi, Roth, David M, Patel, Hemal H, Patel, Piyush M, Tadokoro, Takahiro, Marsala, Martin, Head, Brian P |
| Prispievatelia: | Shanshan Wang, Taiga Ichinomiya, Paul Savchenko, Dongsheng Wang, Atsushi Sawada, Xiaojing Li, Tiffany Duong, Wenxi Li, Jacqueline A Bonds, Eun Jung Kim, Atsushi Miyanohara, David M Roth, Hemal H Patel, Piyush M Patel, Takahiro Tadokoro, Martin Marsala, Brian P Head, Kim, Eun Jung |
| Zdroj: | Theranostics Theranostics, vol 12, iss 12 |
| Informácie o vydavateľovi: | Ivyspring International Publisher, 2022. |
| Rok vydania: | 2022 |
| Predmety: | Male, 0301 basic medicine, amyotrophic lateral sclerosis, Medical Biotechnology, Caveolin 1, Neurodegenerative, 01 natural sciences, Transgenic, Motor Neurons / metabolism, Mice, 0302 clinical medicine, 2.1 Biological and endogenous factors, membrane/lipid raft, Motor Neurons, Dependovirus / genetics, neuromuscular junction, hSOD1G93A, Gene Transfer Techniques, Gene Therapy, Dependovirus, gene therapy, Synapsins* / genetics, 3. Good health, Synapsins* / therapeutic use, Superoxide Dismutase / genetics, Neurological, Superoxide Dismutase / metabolism, Female, Neuromuscular Junction / metabolism, Synapsins* / metabolism, Biotechnology, Research Paper, caveolin-1, Oncology and Carcinogenesis, Neuromuscular Junction, Mice, Transgenic, Amyotrophic Lateral Sclerosis* / therapy, 03 medical and health sciences, Rare Diseases, Caveolin 1* / genetics, Genetics, Animals, Humans, membrane/lipid raft (MLRs), Dependovirus / metabolism, motor neuron, Caveolin 1* / metabolism, Biomedical and Clinical Sciences, Caveolin 1* / therapeutic use, Animal, Superoxide Dismutase, Amyotrophic Lateral Sclerosis, Neurosciences, Oncology and carcinogenesis, Synapsins, Brain Disorders, 0104 chemical sciences, Rats, Disease Models, Animal, Orphan Drug, Amyotrophic Lateral Sclerosis* / genetics, Disease Models, hSOD1(G93A), ALS |
| Popis: | Elevating neuroprotective proteins using adeno-associated virus (AAV)-mediated gene delivery shows great promise in combating devastating neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS) is one such disease resulting from loss of upper and lower motor neurons (MNs) with 90-95% of cases sporadic (SALS) in nature. Due to the unknown etiology of SALS, interventions that afford neuronal protection and preservation are urgently needed. Caveolin-1 (Cav-1), a membrane/lipid rafts (MLRs) scaffolding and neuroprotective protein, and MLR-associated signaling components are decreased in degenerating neurons in postmortem human brains. We previously showed that, when crossing our SynCav1 transgenic mouse (TG) with the mutant human superoxide dismutase 1 (hSOD1G93A) mouse model of ALS, the double transgenic mouse (SynCav1 TG/hSOD1G93A) exhibited better motor function and longer survival. The objective of the current study was to test whether neuron-targeted Cav-1 upregulation in the spinal cord using AAV9-SynCav1 could improve motor function and extend longevity in mutant humanized mouse and rat (hSOD1G93A) models of familial (F)ALS. Methods: Motor function was assessed by voluntary running wheel (RW) in mice and forelimb grip strength (GS) and motor evoked potentials (MEP) in rats. Immunofluorescence (IF) microscopy for choline acetyltransferase (ChAT) was used to assess MN morphology. Neuromuscular junctions (NMJs) were measured by bungarotoxin-a (Btx-a) and synaptophysin IF. Body weight (BW) was measured weekly, and the survival curve was determined by Kaplan-Meier analysis. Results: Following subpial gene delivery to the lumbar spinal cord, male and female hSOD1G93A mice treated with SynCav1 exhibited delayed disease onset, greater running-wheel performance, preserved spinal alpha-motor neuron morphology and NMJ integrity, and 10% increased longevity, independent of affecting expression of the mutant hSOD1G93A protein. Cervical subpial SynCav1 delivery to hSOD1G93A rats preserved forelimb GS and MEPs in the brachial and gastrocnemius muscles. Conclusion: In summary, subpial delivery of SynCav1 protects and preserves spinal motor neurons, and extends longevity in a familial mouse model of ALS without reducing the toxic monogenic component. Furthermore, subpial SynCav1 delivery preserved neuromuscular function in a rat model of FALS. The latter findings strongly indicate the therapeutic applicability of SynCav1 to treat ALS attributed to monogenic (FALS) and potentially in sporadic cases (i.e., SALS). |
| Druh dokumentu: | Article Other literature type |
| Popis súboru: | application/pdf |
| Jazyk: | English |
| ISSN: | 1838-7640 |
| DOI: | 10.7150/thno.72614 |
| Prístupová URL adresa: | https://pubmed.ncbi.nlm.nih.gov/35910808 https://escholarship.org/content/qt68f3p9hv/qt68f3p9hv.pdf https://escholarship.org/uc/item/68f3p9hv |
| Rights: | CC BY NC ND CC BY URL: http://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. |
| Prístupové číslo: | edsair.doi.dedup.....dd8bbb0ce2f94d55747c848a4625daea |
| Databáza: | OpenAIRE |
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Nájsť tento článok vo Web of Science | Abstrakt: | Elevating neuroprotective proteins using adeno-associated virus (AAV)-mediated gene delivery shows great promise in combating devastating neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS) is one such disease resulting from loss of upper and lower motor neurons (MNs) with 90-95% of cases sporadic (SALS) in nature. Due to the unknown etiology of SALS, interventions that afford neuronal protection and preservation are urgently needed. Caveolin-1 (Cav-1), a membrane/lipid rafts (MLRs) scaffolding and neuroprotective protein, and MLR-associated signaling components are decreased in degenerating neurons in postmortem human brains. We previously showed that, when crossing our SynCav1 transgenic mouse (TG) with the mutant human superoxide dismutase 1 (hSOD1G93A) mouse model of ALS, the double transgenic mouse (SynCav1 TG/hSOD1G93A) exhibited better motor function and longer survival. The objective of the current study was to test whether neuron-targeted Cav-1 upregulation in the spinal cord using AAV9-SynCav1 could improve motor function and extend longevity in mutant humanized mouse and rat (hSOD1G93A) models of familial (F)ALS. Methods: Motor function was assessed by voluntary running wheel (RW) in mice and forelimb grip strength (GS) and motor evoked potentials (MEP) in rats. Immunofluorescence (IF) microscopy for choline acetyltransferase (ChAT) was used to assess MN morphology. Neuromuscular junctions (NMJs) were measured by bungarotoxin-a (Btx-a) and synaptophysin IF. Body weight (BW) was measured weekly, and the survival curve was determined by Kaplan-Meier analysis. Results: Following subpial gene delivery to the lumbar spinal cord, male and female hSOD1G93A mice treated with SynCav1 exhibited delayed disease onset, greater running-wheel performance, preserved spinal alpha-motor neuron morphology and NMJ integrity, and 10% increased longevity, independent of affecting expression of the mutant hSOD1G93A protein. Cervical subpial SynCav1 delivery to hSOD1G93A rats preserved forelimb GS and MEPs in the brachial and gastrocnemius muscles. Conclusion: In summary, subpial delivery of SynCav1 protects and preserves spinal motor neurons, and extends longevity in a familial mouse model of ALS without reducing the toxic monogenic component. Furthermore, subpial SynCav1 delivery preserved neuromuscular function in a rat model of FALS. The latter findings strongly indicate the therapeutic applicability of SynCav1 to treat ALS attributed to monogenic (FALS) and potentially in sporadic cases (i.e., SALS). |
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| ISSN: | 18387640 |
| DOI: | 10.7150/thno.72614 |