title: Delayed disease onset and extended survival in the SOD1G93A rat model of amyotrophic lateral sclerosis after suppression of mutant SOD1 in the motor cortex.
abstract: Sporadic amyotrophic lateral sclerosis (ALS) is a fatal disease with unknown etiology, characterized by a progressive loss of motor neurons leading to paralysis and death typically within 3-5 years of onset. Recently, there has been remarkable progress in understanding inherited forms of ALS in which well defined mutations are known to cause the disease. Rodent models in which the superoxide dismutase-1 (SOD1) mutation is overexpressed recapitulate hallmark signs of ALS in patients. Early anatomical changes in mouse models of fALS are seen in the neuromuscular junctions (NMJs) and lower motor neurons, and selective reduction of toxic mutant SOD1 in the spinal cord and muscle of these models has beneficial effects. Therefore, much of ALS research has focused on spinal motor neuron and NMJ aspects of the disease. Here we show that, in the SOD1(G93A) rat model of ALS, spinal motor neuron loss occurs presymptomatically and before degeneration of ventral root axons and denervation of NMJs. Although overt cell death of corticospinal motor neurons does not occur until disease endpoint, we wanted to establish whether the upper motor neuron might still play a critical role in disease progression. Surprisingly, the knockdown of mutant SOD1 in only the motor cortex of presymptomatic SOD1(G93A) rats through targeted delivery of AAV9-SOD1-shRNA resulted in a significant delay of disease onset, expansion of lifespan, enhanced survival of spinal motor neurons, and maintenance of NMJs. This datum suggests an early dysfunction and thus an important role of the upper motor neuron in this animal model of ALS and perhaps patients with the disease.
authors.affiliation: Board of Governors Regenerative Medicine Institute.
authors.forename: Gretchen M
authors.initials: GM
authors.lastname: Thomsen
authors.affiliation: Board of Governors Regenerative Medicine Institute.
authors.forename: Genevieve
authors.identifier: http://orcid.org/0000-0003-3390-9416
authors.initials: G
authors.lastname: Gowing
authors.affiliation: Board of Governors Regenerative Medicine Institute.
authors.forename: Jessica
authors.initials: J
authors.lastname: Latter
authors.affiliation: Board of Governors Regenerative Medicine Institute.
authors.forename: Maximus
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Biomedical Sciences, and Biobehavioral Research Core, Cedars-Sinai Medical Center, Los Angeles, California 90048.
authors.forename: Jean-Philippe
authors.identifier: http://orcid.org/0000-0001-5057-8554
authors.initials: JP
authors.lastname: Vit
authors.affiliation: Board of Governors Regenerative Medicine Institute.
authors.forename: Kevin
authors.initials: K
authors.lastname: Staggenborg
authors.affiliation: Board of Governors Regenerative Medicine Institute.
authors.forename: Pablo
authors.initials: P
authors.lastname: Avalos
authors.affiliation: Board of Governors Regenerative Medicine Institute.
authors.forename: Mor
authors.initials: M
authors.lastname: Alkaslasi
authors.affiliation: Center for Gene Therapy, Research Institute at Nationwide Children's Hospital, Columbus, Ohio 43205, and.
authors.forename: Laura
authors.initials: L
authors.lastname: Ferraiuolo
authors.affiliation: Center for Gene Therapy, Research Institute at Nationwide Children's Hospital, Columbus, Ohio 43205, and.
authors.forename: Shibi
authors.initials: S
authors.lastname: Likhite
authors.affiliation: Center for Gene Therapy, Research Institute at Nationwide Children's Hospital, Columbus, Ohio 43205, and Department of Neuroscience, Ohio State University, Columbus, Ohio 43210.
authors.forename: Brian K
authors.identifier: http://orcid.org/0000-0003-2394-0196
authors.initials: BK
authors.lastname: Kaspar
authors.affiliation: Board of Governors Regenerative Medicine Institute, Department of Biomedical Sciences, and Clive.Svendsen@cshs.org.
authors.forename: Clive N
authors.initials: CN
authors.lastname: Svendsen
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D005260:Female; D055785:Gene Knockdown Techniques; D011558:Herpesvirus 1, Suid / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D009044:Motor Cortex / Q000201:enzymology* / Q000473:pathology*; D009469:Neuromuscular Junction / Q000187:drug effects; D009474:Neurons / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D013482:Superoxide Dismutase / Q000235:genetics* / Q000502:physiology*; D000072105:Superoxide Dismutase-1; D014162:Transfection
chemical_list: C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
keywords: ALS; RNAi; SOD1; amyotrophic lateral sclerosis; motor neuron disease; neurodegenerative disorder