title: SMN expression is required in motor neurons to rescue electrophysiological deficits in the SMNΔ7 mouse model of SMA.
abstract: Proximal spinal muscular atrophy (SMA) is the most frequent cause of hereditary infant mortality. SMA is an autosomal recessive neuromuscular disorder that results from the loss of the Survival Motor Neuron 1 (SMN1) gene and retention of the SMN2 gene. The SMN2 gene produces an insufficient amount of full-length SMN protein that results in loss of motor neurons in the spinal cord and subsequent muscle paralysis. Previously we have shown that overexpression of human SMN in neurons in the SMA mouse ameliorates the SMA phenotype while overexpression of human SMN in skeletal muscle had no effect. Using Cre recombinase, here we show that either deletion or replacement of Smn in motor neurons (ChAT-Cre) significantly alters the functional output of the motor unit as measured with compound muscle action potential and motor unit number estimation. However ChAT-Cre alone did not alter the survival of SMA mice by replacement and did not appreciably affect survival when used to deplete SMN. However replacement of Smn in both neurons and glia in addition to the motor neuron (Nestin-Cre and ChAT-Cre) resulted in the greatest improvement in survival of the mouse and in some instances complete rescue was achieved. These findings demonstrate that high expression of SMN in the motor neuron is both necessary and sufficient for proper function of the motor unit. Furthermore, in the mouse high expression of SMN in neurons and glia, in addition to motor neurons, has a major impact on survival.
authors.affiliation: Department of Molecular and Cellular Biochemistry, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
authors.forename: Vicki L
authors.initials: VL
authors.lastname: McGovern
authors.affiliation: Department of Molecular and Cellular Biochemistry, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
authors.forename: Chitra C
authors.initials: CC
authors.lastname: Iyer
authors.affiliation: Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA Department of Physical Medicine and Rehabilitation, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA and.
authors.forename: W David
authors.initials: WD
authors.lastname: Arnold
authors.affiliation: Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA and.
authors.forename: Sara E
authors.initials: SE
authors.lastname: Gombash
authors.affiliation: PharmOptima, LLC, Portage, MI 49002, USA.
authors.forename: Phillip G
authors.initials: PG
authors.lastname: Zaworski
authors.affiliation: Department of Molecular and Cellular Biochemistry, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
authors.forename: Anton J
authors.initials: AJ
authors.lastname: Blatnik
authors.affiliation: Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA and.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Foust
authors.affiliation: Department of Molecular and Cellular Biochemistry, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA burghes.1@osu.edu.
authors.forename: Arthur H M
authors.initials: AH
authors.lastname: Burghes
mesh_terms: D000200:Action Potentials; D000818:Animals; D004195:Disease Models, Animal; D055724:Electrophysiological Phenomena; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism / Q000502:physiology*; D018482:Muscle, Skeletal / Q000502:physiology*; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D017384:Sequence Deletion; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics* / Q000378:metabolism*
chemical_list: C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein