Astrocytes influence the severity of spinal muscular atrophy. Hum Mol Genet 2015 Jul 15;24(14):4094-102
Date
04/26/2015Pubmed ID
25911676Pubmed Central ID
PMC5007659DOI
10.1093/hmg/ddv148Scopus ID
2-s2.0-84936741397 (requires institutional sign-in at Scopus site) 89 CitationsAbstract
Systemically low levels of survival motor neuron-1 (SMN1) protein cause spinal muscular atrophy (SMA). α-Motor neurons of the spinal cord are considered particularly vulnerable in this genetic disorder and their dysfunction and loss cause progressive muscle weakness, paralysis and eventually premature death of afflicted individuals. Historically, SMA was therefore considered a motor neuron-autonomous disease. However, depletion of SMN in motor neurons of normal mice elicited only a very mild phenotype. Conversely, restoration of SMN to motor neurons in an SMA mouse model had only modest effects on the SMA phenotype and survival. Collectively, these results suggested that additional cell types contribute to the pathogenesis of SMA, and understanding the non-autonomous requirements is crucial for developing effective therapies. Astrocytes are critical for regulating synapse formation and function as well as metabolic support for neurons. We hypothesized that astrocyte functions are disrupted in SMA, exacerbating disease progression. Using viral-based restoration of SMN specifically to astrocytes, survival in severe and intermediate SMA mice was observed. In addition, neuromuscular circuitry was improved. Astrogliosis was prominent in end-stage SMA mice and in post-mortem patient spinal cords. Increased expression of proinflammatory cytokines was partially normalized in treated mice, suggesting that astrocytes contribute to the pathogenesis of SMA.
Author List
Rindt H, Feng Z, Mazzasette C, Glascock JJ, Valdivia D, Pyles N, Crawford TO, Swoboda KJ, Patitucci TN, Ebert AD, Sumner CJ, Ko CP, Lorson CLAuthors
Allison D. Ebert PhD Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinTeresa Patitucci PhD Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsAstrocytes
Cell Differentiation
Dependovirus
Disease Models, Animal
Gene Expression Regulation
Genetic Vectors
Humans
Induced Pluripotent Stem Cells
Mice
Mice, Inbred C57BL
Mice, Knockout
Motor Neurons
Muscular Atrophy, Spinal
Neuromuscular Junction
Phenotype
Spinal Cord
Survival of Motor Neuron 1 Protein