Journal
FASEB JOURNAL
Volume 33, Issue 6, Pages 7545-7554Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.201802652RR
Keywords
neuroplasticity; motor neurons; MLR; TrkB; mitochondria
Categories
Funding
- U.S. National Institutes of Health (NIH) Office of the Director Award [S10OD023527]
- Veteran Affairs Merit Award from the Department of Veterans Affairs [BX003671, BX000783, BX001963]
- NIH National Institute of Neurological Disorders and Stroke [NS073653]
- NIH National Heart, Lung, and Blood Institute [HL091071, HL107200]
- NIH National Institute of General Medical Sciences [GM085179]
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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 overexpression 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 (hSOD1(G93A)) mouse model of ALS. When compared with hSOD1(G93A), hSOD1(G93A)/SynCav1(+) mice exhibited greater body weight and longer survival as well as better motor function. Microscopic analyses of hSOD1(G93A)/SynCav1(+) spinal cords revealed preserved spinal cord alpha-motor neurons and preserved mitochondrial morphology. Moreover, hSOD1(G93A)/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 SOD1(G93A) mice.
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