title: Selective forelimb impairment in rats expressing a pathological TDP-43 25 kDa C-terminal fragment to mimic amyotrophic lateral sclerosis.
abstract: Pathological inclusions containing transactive response DNA-binding protein 43 kDa (TDP-43) are common in several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). TDP-43 normally localizes predominantly to the nucleus, but during disease progression, it mislocalizes to the cytoplasm. We expressed TDP-43 in rats by an adeno-associated virus (AAV9) gene transfer method that transduces neurons throughout the central nervous system (CNS). To mimic the aberrant cytoplasmic TDP-43 found in disease, we expressed a form of TDP-43 with mutations in the nuclear localization signal sequence (TDP-NLS). The TDP-NLS was detected in both the cytoplasm and the nucleus of transduced neurons. Unlike wild-type TDP-43, expression of TDP-NLS did not induce mortality. However, the TDP-NLS induced disease-relevant motor impairments over 24 weeks. We compared the TDP-NLS to a 25 kDa C-terminal proaggregatory fragment of TDP-43 (TDP-25). The clinical phenotype of forelimb impairment was pronounced with the TDP-25 form, supporting a role of this C-terminal fragment in pathogenesis. The results advance previous rodent models by inducing cytoplasmic expression of TDP-43 in the spinal cord, and the non-lethal phenotype enabled long-term study. Approaching a more relevant disease state in an animal model that more closely mimics underlying mechanisms in human disease could unlock our ability to develop therapeutics.
authors.affiliation: Department of Pharmacology, Toxicology, and Neuroscience, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Dayton
authors.forename: Michael A
authors.initials: MA
authors.lastname: Gitcho
authors.forename: Elysse A
authors.initials: EA
authors.lastname: Orchard
authors.forename: Jon D
authors.initials: JD
authors.lastname: Wilson
authors.forename: David B
authors.initials: DB
authors.lastname: Wang
authors.forename: Cooper D
authors.initials: CD
authors.lastname: Cain
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Johnson
authors.forename: Yong-Jie
authors.initials: YJ
authors.lastname: Zhang
authors.forename: Leonard
authors.initials: L
authors.lastname: Petrucelli
authors.forename: J Michael
authors.initials: JM
authors.lastname: Mathis
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Klein
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D015153:Blotting, Western; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000229:Dependovirus / Q000235:genetics; D005260:Female; D005552:Forelimb / Q000378:metabolism* / Q000473:pathology*; D007150:Immunohistochemistry; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology
chemical_list: D004268:DNA-Binding Proteins