title: Functional recovery in new mouse models of ALS/FTLD after clearance of pathological cytoplasmic TDP-43.
abstract: Accumulation of phosphorylated cytoplasmic TDP-43 inclusions accompanied by loss of normal nuclear TDP-43 in neurons and glia of the brain and spinal cord are the molecular hallmarks of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP). However, the role of cytoplasmic TDP-43 in the pathogenesis of these neurodegenerative TDP-43 proteinopathies remains unclear, due in part to a lack of valid mouse models. We therefore generated new mice with doxycycline (Dox)-suppressible expression of human TDP-43 (hTDP-43) harboring a defective nuclear localization signal (∆NLS) under the control of the neurofilament heavy chain promoter. Expression of hTDP-43∆NLS in these 'regulatable NLS' (rNLS) mice resulted in the accumulation of insoluble, phosphorylated cytoplasmic TDP-43 in brain and spinal cord, loss of endogenous nuclear mouse TDP-43 (mTDP-43), brain atrophy, muscle denervation, dramatic motor neuron loss, and progressive motor impairments leading to death. Notably, suppression of hTDP-43∆NLS expression by return of Dox to rNLS mice after disease onset caused a dramatic decrease in phosphorylated TDP-43 pathology, an increase in nuclear mTDP-43 to control levels, and the prevention of further motor neuron loss. rNLS mice back on Dox also showed a significant increase in muscle innervation, a rescue of motor impairments, and a dramatic extension of lifespan. Thus, the rNLS mice are new TDP-43 mouse models that delineate the timeline of pathology development, muscle denervation and neuron loss in ALS/FTLD-TDP. Importantly, even after neurodegeneration and onset of motor dysfunction, removal of cytoplasmic TDP-43 and the concomitant return of nuclear TDP-43 led to neuron preservation, muscle re-innervation and functional recovery.
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Adam K
authors.initials: AK
authors.lastname: Walker
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Krista J
authors.initials: KJ
authors.lastname: Spiller
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Guanghui
authors.initials: G
authors.lastname: Ge
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Allen
authors.initials: A
authors.lastname: Zheng
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Kalyan
authors.initials: K
authors.lastname: Tripathy
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Linda K
authors.initials: LK
authors.lastname: Kwong
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.|Institute on Aging, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. vmylee@upenn.edu.|Institute on Aging, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. vmylee@upenn.edu.
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D001284:Atrophy; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D003593:Cytoplasm / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004318:Doxycycline; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D008297:Male; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009069:Movement Disorders / Q000473:pathology / Q000503:physiopathology; D018482:Muscle, Skeletal / Q000294:innervation; D011897:Random Allocation; D020127:Recovery of Function / Q000502:physiology*; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology
chemical_list: D004268:DNA-Binding Proteins; C000598624:TARDBP protein, human; D004318:Doxycycline
keywords: Amyotrophic lateral sclerosis (ALS); Frontotemporal dementia (FTD); Frontotemporal lobar degeneration (FTLD); Motor neuron; Mouse model; Neurodegeneration; Spinal cord; TDP-43