Neuron‐targeted caveolin‐1 improves neuromuscular function and extends survival in SOD1 ^G93A mice

Abstract

Interventions that preserve motor neurons or restore functional motor neuroplasticity may extend longevity in amyotrophic lateral sclerosis (ALS). Delivery of neurotrophins may potentially revive degenerating motor neurons, yet this approach is dependent on the proper subcellular localization of neurotrophin receptor (NTR) to plasmalemmal signaling microdomains, termed membrane/lipid rafts (MLRs). We previously showed that over‐expression of synapsin‐driven caveolin‐1 (Cav‐1) (SynCav1) increases MLR localization of NTR [e.g., receptor tyrosine kinase B (TrkB)], promotes hippocampal synaptic and neuroplasticity, and significantly improves learning and memory in aged mice. The present study crossed a SynCav1 transgene‐positive (SynCav1+) mouse with the mutant human superoxide dismutase glycine to alanine point mutation at amino acid 93 (hSOD1G93A) mouse model of ALS. When compared with hSOD1G93A, hSOD1G93A/SynCav1+ mice exhibited greater body weight and longer survival as well as better motor function. Microscopic analyses of hSOD1G93A/SynCav1+ spinal cords revealed preserved spinal cord α‐motor neurons and preserved mitochondrial morphology. Moreover, hSOD1G93A/SynCav1+ spinal cords contained more MLRs (cholera toxin subunit B positive) and MLR‐associated TrkB and Cav‐1 protein expression. These findings demonstrate that SynCav1 delays disease progression in a mouse model of ALS, potentially by preserving or restoring NTR expression and localization to MLRs.—Sawada, A., Wang, S., Jian, M., Leem, J., Wackerbarth, J., Egawa, J., Schilling, J. M., Platoshyn, O., Zemljic‐Harpf, A., Roth, D. M., Patel, H. H., Patel, P. M., Marsala, M., Head, B. P. Neuron‐targeted caveolin‐1 improves neuromuscular function and extends survival in SOD1G93A mice. FASEB J. 33, 7545–7554 (2019). http://www.fasebj.org

Synapsin-caveolin-1 Mitigates Cognitive Deficits and Neurodegeneration in PSAPP Mice

“…Furthermore, SynCav1 preserved MLR-localization of protein markers of neuronal and synaptic plasticity, all of which occurred independent of removing neurotoxic Ab plaques or reducing astrogliosis. This study builds upon previous work demonstrating the neuroprotective effects of SynCav1 gene therapy in the setting of aging, traumatic brain injury, and ALS [13,14,19], and now further extends the therapeutic potential of SynCav1 in another neurodegenerative disease indication, i.e., the PSAPP transgenic model of AD.…”

“…Both pre-clinical and clinical findings revealed that Cav-1 and Cav-1 associated signaling complexes (NTRs and neurotransmitter receptors) were decreased in degenerating neurons in AD, chronic traumatic encephalopathy (CTE), and amyotrophic lateral sclerosis (ALS) [15][16][17][18]. In contrast, we previously showed that neuron-targeted Cav-1 over-expression (i.e., synapsin-promoted Cav-1 or SynCav1) augmented agonist-mediated synaptic signaling (e.g., NTRs, neurotransmitter receptors) and dendritic arborization in vitro [12], preserved MLR-localized TrkB and extended life span in ALS mice [19], suggesting that alterations in Cav-1 expression affects pro-survival signaling and neuroprotection in neurodegenerative conditions .…”

Synapsin-caveolin-1 mitigates cognitive deficits and neurodegeneration in Alzheimer’s disease mice

“…Furthermore, SynCav1 preserved MLR-localization of protein markers of neuronal and synaptic plasticity, all of which occurred independent of removing neurotoxic Ab plaques or reducing astrogliosis. This study builds upon previous work demonstrating the neuroprotective effects of SynCav1 gene therapy in the setting of aging, traumatic brain injury, and ALS(Egawa et al, 2017; Mandyam et al, 2017; Sawada et al, 2019), and now further extends the therapeutic potential of SynCav1 in another neurodegenerative disease indication, i.e., the PSAPP transgenic model of AD.…”

“…Both pre-clinical and clinical findings revealed that Cav-1 and Cav-1 associated signaling complexes (NTRs and neurotransmitter receptors) were decreased in degenerating neurons in AD, chronic traumatic encephalopathy (CTE), and amyotrophic lateral sclerosis (ALS)(Flis et al, 2018; Mufson et al, 2018; Tiernan et al, 2018; Yuan et al, 2017). In contrast, we previously showed that neuron-targeted Cav-1 over-expression (i.e., synapsin-promoted Cav-1 or SynCav1 ) augmented agonist-mediated synaptic signaling (e.g., NTRs, neurotransmitter receptors) and dendritic arborization in vitro (Head et al, 2011), preserved MLR-localized TrkB and extended life span in ALS mice(Sawada et al, 2019), suggesting that alterations in Cav-1 expression affects pro-survival signaling and neuroprotection in neurodegenerative conditions.…”

Caveolin-1 and MLRs: A potential target for neuronal growth and neuroplasticity after ischemic stroke

“…Many neurodegeneration studies have shown that neuron-targeted overexpression of Cav-1 increased MLR formation, pro-growth receptor localization to MLRs, myelination, and long-term potentiation, resulting in neuronal development and regeneration 20-23. Furthermore, synapsin-driven overexpression of Cav-1 was shown to preserve and restore NT-receptors expression and localization to MLRs, resulting in delayed progression of ALS in a mouse model 24. These studies suggested that Cav-1 and MLRs may be potential therapeutic targets to promote neuroplasticity in neurological disorders.…”