Please use this identifier to cite or link to this item: https://doi.org/10.1007/s00401-017-1698-6
Title: Mutant TDP-43 within motor neurons drives disease onset but not progression in amyotrophic lateral sclerosis
Authors: Ditsworth, D
Maldonado, M
McAlonis-Downes, M
Sun, S
Seelman, A
Drenner, K
Arnold, E
Ling, S.-C 
Pizzo, D
Ravits, J
Cleveland, D.W
Da Cruz, S
Keywords: cre recombinase
mutant protein
TAR DNA binding protein
DNA binding protein
TDP-43 protein, human
allele
amyotrophic lateral sclerosis
animal cell
animal experiment
animal model
animal tissue
Article
astrocytosis
axon
controlled study
disease course
gene expression
gene mutation
gliosis
human
human tissue
motoneuron
mouse
nerve cell degeneration
nerve cell necrosis
neuromuscular junction
nonhuman
priority journal
adult
aging
amyotrophic lateral sclerosis
animal
C57BL mouse
disease exacerbation
disease model
female
genetics
inflammation
male
metabolism
middle aged
motoneuron
motor activity
mutation
pathology
physiology
transgenic mouse
very elderly
young adult
Adult
Aged, 80 and over
Aging
Amyotrophic Lateral Sclerosis
Animals
Disease Models, Animal
Disease Progression
DNA-Binding Proteins
Female
Humans
Inflammation
Male
Mice, Inbred C57BL
Mice, Transgenic
Middle Aged
Motor Activity
Motor Neurons
Mutation
Neuromuscular Junction
Young Adult
Issue Date: 2017
Publisher: Springer Verlag
Citation: Ditsworth, D, Maldonado, M, McAlonis-Downes, M, Sun, S, Seelman, A, Drenner, K, Arnold, E, Ling, S.-C, Pizzo, D, Ravits, J, Cleveland, D.W, Da Cruz, S (2017). Mutant TDP-43 within motor neurons drives disease onset but not progression in amyotrophic lateral sclerosis. Acta Neuropathologica 133 (6) : 907-922. ScholarBank@NUS Repository. https://doi.org/10.1007/s00401-017-1698-6
Rights: Attribution 4.0 International
Abstract: Mutations in TDP-43 cause amyotrophic lateral sclerosis (ALS), a fatal paralytic disease characterized by degeneration and premature death of motor neurons. The contribution of mutant TDP-43-mediated damage within motor neurons was evaluated using mice expressing a conditional allele of an ALS-causing TDP-43 mutant (Q331K) whose broad expression throughout the central nervous system mimics endogenous TDP-43. TDP-43Q331K mice develop age- and mutant-dependent motor deficits from degeneration and death of motor neurons. Cre-recombinase-mediated excision of the TDP-43Q331K gene from motor neurons is shown to delay onset of motor symptoms and appearance of TDP-43-mediated aberrant nuclear morphology, and abrogate subsequent death of motor neurons. However, reduction of mutant TDP-43 selectively in motor neurons did not prevent age-dependent degeneration of axons and neuromuscular junction loss, nor did it attenuate astrogliosis or microgliosis. Thus, disease mechanism is non-cell autonomous with mutant TDP-43 expressed in motor neurons determining disease onset but progression defined by mutant acting within other cell types. © 2017, The Author(s).
Source Title: Acta Neuropathologica
URI: https://scholarbank.nus.edu.sg/handle/10635/179201
ISSN: 00016322
DOI: 10.1007/s00401-017-1698-6
Rights: Attribution 4.0 International
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