Motor Neuron Rescue in Spinal Muscular Atrophy Mice Demonstrates That Sensory-Motor Defects Are a Consequence, Not a Cause, of Motor Neuron Dysfunction

@article{Gogliotti2012MotorNR,
  title={Motor Neuron Rescue in Spinal Muscular Atrophy Mice Demonstrates That Sensory-Motor Defects Are a Consequence, Not a Cause, of Motor Neuron Dysfunction},
  author={Rocky G. Gogliotti and K. A. Quinlan and Courtenay B Barlow and Christoph Heier and Charles J. Heckman and Christine J DiDonato},
  journal={The Journal of Neuroscience},
  year={2012},
  volume={32},
  pages={3818 - 3829}
}
The loss of motor neurons (MNs) is a hallmark of the neuromuscular disease spinal muscular atrophy (SMA); however, it is unclear whether this phenotype autonomously originates within the MN. To address this question, we developed an inducible mouse model of severe SMA that has perinatal lethality, decreased motor function, motor unit pathology, and hyperexcitable MNs. Using an Hb9-Cre allele, we increased Smn levels autonomously within MNs and demonstrate that MN rescue significantly improves… Expand
Improvement of Neuromuscular Synaptic Phenotypes without Enhanced Survival and Motor Function in Severe Spinal Muscular Atrophy Mice Selectively Rescued in Motor Neurons
TLDR
The results directly suggest that even those therapeutic interventions with very modest effects in raising SMN in motor neurons may provide mitigation of neuromuscular phenotypes in SMA patients. Expand
Motor Neuron-Specific Restoration of SMN in Two SMA Mouse Models: Insights into the Role of Motor Neurons in Spinal Muscular Atrophy
TLDR
Exogenously raised normal human SMN in severe SMA mice that die perinatally and increased endogenous motor neuronal-SMN expression following embryonic Hb9-dependent Cre recombination of a conditional hybrid mutant allele (Smn res) in anothersevere SMA mouse model (SMA7-like). Expand
Motor neuron cell-nonautonomous rescue of spinal muscular atrophy phenotypes in mild and severe transgenic mouse models.
TLDR
The data demonstrate a critical role of peripheral pathology in the mortality of SMA mice and indicate that peripheral SMN restoration compensates for its deficiency in the CNS and preserves motor neurons, indicating that SMA is not a cell-autonomous defect of motor neurons in S MA mice. Expand
Astrocytes influence the severity of spinal muscular atrophy.
TLDR
Using viral-based restoration of SMN specifically to astrocytes, survival in severe and intermediate SMA mice was observed and increased expression of proinflammatory cytokines was partially normalized in treated mice, suggesting that Astrocytes contribute to the pathogenesis of SMA. Expand
Is spinal muscular atrophy a disease of the motor neurons only: pathogenesis and therapeutic implications?
TLDR
It has been demonstrated that non-motor neuronal cells are also involved in disease pathogenesis and could have important therapeutic implications and it will be crucial to take this evidence into account for the clinical translation of the novel therapeutic approaches. Expand
Survival Motor Neuron Protein in Motor Neurons Determines Synaptic Integrity in Spinal Muscular Atrophy
TLDR
The data suggest that SMN plays distinct roles in muscle, NMJs, and motor neuron somal synapses and that restored function of SMN at all three sites will be necessary for full recovery of muscle power. Expand
SMN Is Required for Sensory-Motor Circuit Function in Drosophila
TLDR
These results establish sensory-motor circuit dysfunction as the origin of motor system deficits in this SMA model and suggest that enhancement of motor neural network activity could ameliorate the disease. Expand
Spinal muscular atrophy: a motor neuron disorder or a multi‐organ disease?
TLDR
Clinical and experimental reports are compiled that demonstrate the association between the loss of SMN and peripheral organ deficiency and malfunction and whether defective peripheral organs are a consequence of neuronal damage/muscle atrophy or a direct result ofSMN loss. Expand
Spinal muscular atrophy astrocytes exhibit abnormal calcium regulation and reduced growth factor production
TLDR
It is shown that astrocytes in SMAΔ7 mouse spinal cord and from SMA‐induced pluripotent stem cells exhibit morphological and cellular changes indicative of activation before overt motor neuron loss, and in vitro studies show mis‐regulation of basal calcium and decreased response to adenosine triphosphate stimulation indicating abnormalAstrocyte function. Expand
Disease Mechanisms and Therapeutic Approaches in Spinal Muscular Atrophy
TLDR
SMA is emerging as an RNA disease not limited to motor neurons, but one that involves dysfunction of motor circuits that comprise multiple neuronal subpopulations and possibly other cell types, and offers unprecedented promise for the treatment of this still incurable neurodegenerative disease. Expand
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