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
Copyright policy )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
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).
- University of California, San Francisco United States
- VA Desert Pacific Healthcare Network United States
- Yonsei University Health System Korea (Republic of)
- Yonsei University Korea (Republic of)
- VA SAN DIEGO HEALTHCARE SYSTEM
Male, amyotrophic lateral sclerosis, Medical Biotechnology, Caveolin 1, Neurodegenerative, Transgenic, Motor Neurons / metabolism, Mice, 2.1 Biological and endogenous factors, membrane/lipid raft, Motor Neurons, Dependovirus / genetics, neuromuscular junction, hSOD1G93A, Gene Transfer Techniques*, Gene Transfer Techniques, Gene Therapy, Dependovirus, gene therapy, Synapsins* / genetics, 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, 610, Mice, Transgenic, Amyotrophic Lateral Sclerosis* / therapy, 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, Rats, Disease Models, Animal, Orphan Drug, Amyotrophic Lateral Sclerosis* / genetics, Disease Models, hSOD1(G93A), ALS
Male, amyotrophic lateral sclerosis, Medical Biotechnology, Caveolin 1, Neurodegenerative, Transgenic, Motor Neurons / metabolism, Mice, 2.1 Biological and endogenous factors, membrane/lipid raft, Motor Neurons, Dependovirus / genetics, neuromuscular junction, hSOD1G93A, Gene Transfer Techniques*, Gene Transfer Techniques, Gene Therapy, Dependovirus, gene therapy, Synapsins* / genetics, 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, 610, Mice, Transgenic, Amyotrophic Lateral Sclerosis* / therapy, 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, Rats, Disease Models, Animal, Orphan Drug, Amyotrophic Lateral Sclerosis* / genetics, Disease Models, hSOD1(G93A), ALS
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