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 hSOD1 G93A mice

作者：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 Maršala, Brian P. Head · 发表于：Theranostics · 年份：2022 · DOI：10.7150/thno.72614 · 被引用次数：19 · 研究领域：Amyotrophic Lateral Sclerosis Research、Neurogenetic and Muscular Disorders Research、Muscle Physiology and Disorders

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 (hSOD1 G93A ) mouse model of ALS, the double transgenic mouse (SynCav1 TG/hSOD1 G93A ) 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 (hSOD1 G93A ) 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 synapto...