IGF-1 delivery to CNS attenuates motor neuron cell death but does not improve motor function in type III SMA mice
Journal
Neurobiology of Disease
Journal Volume
45
Journal Issue
1
Pages
272-279
Date Issued
2012
Author(s)
Abstract
The efficacy of administering a recombinant adeno-associated virus (AAV) vector encoding human IGF-1 (AAV2/1-hIGF-1) into the deep cerebellar nucleus (DCN) of a type III SMA mouse model was evaluated. High levels of IGF-1 transcripts and protein were detected in the spinal cord at 2. months post-injection demonstrating that axonal connections between the cerebellum and spinal cord were able to act as conduits for the viral vector and protein to the spinal cord. Mice treated with AAV2/1-hIGF-1 and analyzed 8. months later showed changes in endogenous Bax and Bcl-xl levels in spinal cord motor neurons that were consistent with IGF-1-mediated anti-apoptotic effects on motor neurons. However, although AAV2/1-hIGF-1 treatment reduced the extent of motor neuron cell death, the majority of rescued motor neurons were non-functional, as they lacked axons that innervated the muscles. Furthermore, treated SMA mice exhibited abnormal muscle fibers, aberrant neuromuscular junction structure, and impaired performance on motor function tests. These data indicate that although CNS-directed expression of IGF-1 could reduce motor neuron cell death, this did not translate to improvements in motor function in an adult mouse model of type III SMA. ? 2011 Elsevier Inc.
SDGs
Other Subjects
parvovirus vector; protein Bax; protein bcl xl; somatomedin C; animal cell; animal experiment; animal model; animal tissue; article; cell count; cell death; cell loss; cerebellum nucleus; controlled study; drug efficacy; motoneuron; motor performance; mouse; nerve fiber; nonhuman; priority journal; protein determination; protein expression; spinal muscular atrophy; treatment response; viral gene delivery system; Animals; Cell Death; Cerebellum; Gene Therapy; Genetic Vectors; Insulin-Like Growth Factor I; Mice; Motor Activity; Motor Neurons; Muscle Fibers, Skeletal; Muscular Atrophy, Spinal; Spinal Cord
Type
journal article