Astrocytes influence the severity of spinal muscular atrophy.
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.
Department of Veterinary Pathobiology and Department of Molecular Microbiology and Immunology, University of Missouri, Bond Life Sciences Center, Columbia, MO 65211, USA.
Hansjörg
H
Rindt
Section of Neurobiology, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA.
Zhihua
Z
Feng
Section of Neurobiology, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA.
Chiara
C
Mazzasette
Department of Veterinary Pathobiology and Department of Molecular Microbiology and Immunology, University of Missouri, Bond Life Sciences Center, Columbia, MO 65211, USA.
Jacqueline J
JJ
Glascock
Departments of Neurology and Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
David
D
Valdivia
Departments of Neurology and Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
Noah
N
Pyles
Departments of Neurology and Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
Thomas O
TO
Crawford
Department of Neurology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA and.
Kathryn J
KJ
Swoboda
Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Teresa N
TN
Patitucci
Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Allison D
AD
Ebert
Departments of Neurology and Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
Charlotte J
CJ
Sumner
Section of Neurobiology, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA.
Chien-Ping
CP
Ko
Department of Veterinary Pathobiology and Department of Molecular Microbiology and Immunology, University of Missouri, Bond Life Sciences Center, Columbia, MO 65211, USA, lorsonc@missouri.edu.
Christian L
CL
Lorson
D000818:Animals; D001253:Astrocytes / Q000166:cytology* / Q000378:metabolism*; D002454:Cell Differentiation; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009046:Motor Neurons / Q000378:metabolism; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000473:pathology*; D009469:Neuromuscular Junction / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D013116:Spinal Cord / Q000378:metabolism; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics / Q000378:metabolism
C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein