title: Severe respiratory changes at end stage in a FUS-induced disease state in adult rats.
abstract: Fused in sarcoma (FUS) is an RNA-binding protein associated with the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration. ALS manifests in patients as a progressive paralysis which leads to respiratory dysfunction and failure, the primary cause of death in ALS. We expressed human FUS in rats to determine if FUS would induce ALS relevant respiratory changes to serve as an early stage disease indicator. The FUS expression was initiated in adult rats by way of an intravenously administered adeno-associated virus vector serotype 9 (AAV9) providing an adult onset model.
  
  
  
  The rats developed progressive motor impairments observed as early as 2-3 weeks post gene transfer. Respiratory abnormalities manifested 4-7 weeks post gene transfer including increased respiratory frequency and decreased tidal volume. Rats with breathing abnormalities also had arterial blood acidosis. Similar detailed plethysmographic changes were found in adult rats injected with AAV9 TDP-43. FUS gene transfer to adult rats yielded a consistent pre-clinical model with relevant motor paralysis in the early to middle stages and respiratory dysfunction at the end stage. Both FUS and TDP-43 yielded a similar consistent disease state.
  
  
  
  This modeling method yields disease relevant motor and respiratory changes in adult rats. The reproducibility of the data supports the use of this method to study other disease related genes and their combinations as well as a platform for disease modifying interventional strategies.
authors: Department of Pharmacology, Toxicology, and Neuroscience, Louisiana State University Health Sciences Center, 1501 Kings Hwy, Shreveport, LA, 71130, USA. kjac12@lsuhsc.edu.
authors: Kasey L
authors: KL
authors: Jackson
authors: Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, 1501 Kings Hwy, Shreveport, LA, 71130, USA.
authors: Hemangini A
authors: HA
authors: Dhaibar
authors: Department of Pharmacology, Toxicology, and Neuroscience, Louisiana State University Health Sciences Center, 1501 Kings Hwy, Shreveport, LA, 71130, USA.
authors: Robert D
authors: RD
authors: Dayton
authors: Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, 1501 Kings Hwy, Shreveport, LA, 71130, USA.
authors: Sergio G
authors: SG
authors: Cananzi
authors: Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, 1501 Kings Hwy, Shreveport, LA, 71130, USA.
authors: William G
authors: WG
authors: Mayhan
authors: Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, 1501 Kings Hwy, Shreveport, LA, 71130, USA.
authors: Edward
authors: E
authors: Glasscock
authors: Department of Pharmacology, Toxicology, and Neuroscience, Louisiana State University Health Sciences Center, 1501 Kings Hwy, Shreveport, LA, 71130, USA.
authors: Ronald L
authors: RL
authors: Klein
mesh_terms: D000138:Acidosis / Q000503:physiopathology; D000690:Amyotrophic Lateral Sclerosis / Q000150:complications / Q000503:physiopathology*; D000818:Animals; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D004924:Escape Reaction / Q000502:physiology; D005260:Female; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology; D009043:Motor Activity / Q000502:physiology; D053580:Muscle Strength / Q000502:physiology; D010243:Paralysis / Q000503:physiopathology; D034702:RNA-Binding Protein FUS / Q000235:genetics / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D012119:Respiration; D012120:Respiration Disorders / Q000209:etiology / Q000503:physiopathology*; D014162:Transfection
chemical_list: C000599550:FUS protein, human; D034702:RNA-Binding Protein FUS; D049452:Green Fluorescent Proteins
keywords: Adeno-associated virus; Amyotrophic lateral sclerosis; FUS; Gene therapy; Respiration; TDP-43