title: Mutant TDP-43 within motor neurons drives disease onset but not progression in amyotrophic lateral sclerosis.
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-43Q331Kmice develop age- and mutant-dependent motor deficits from degeneration and death of motor neurons. Cre-recombinase-mediated excision of the TDP-43Q331Kgene 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.
authors.affiliation: Ludwig Institute for Cancer Research, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0670, USA.|Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0670, USA.
authors.forename: Dara
authors.initials: D
authors.lastname: Ditsworth
authors.affiliation: Ludwig Institute for Cancer Research, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0670, USA.
authors.forename: Marcus
authors.initials: M
authors.lastname: Maldonado
authors.affiliation: Ludwig Institute for Cancer Research, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0670, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: McAlonis-Downes
authors.affiliation: Ludwig Institute for Cancer Research, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0670, USA.|Department of Pathology, Johns Hopkins University, Baltimore, MD, 21205, USA.
authors.forename: Shuying
authors.initials: S
authors.lastname: Sun
authors.affiliation: Ludwig Institute for Cancer Research, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0670, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Seelman
authors.affiliation: Ludwig Institute for Cancer Research, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0670, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Drenner
authors.affiliation: Ludwig Institute for Cancer Research, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0670, USA.
authors.forename: Eveline
authors.initials: E
authors.lastname: Arnold
authors.affiliation: Ludwig Institute for Cancer Research, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0670, USA.|Department of Physiology, National University of Singapore, Singapore, 117549, Singapore.|Program in Neuroscience and Behavior Disorders, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Shuo-Chien
authors.initials: SC
authors.lastname: Ling
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, CA, 92093, USA.
authors.forename: Donald
authors.initials: D
authors.lastname: Pizzo
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, CA, 92093, USA.
authors.forename: John
authors.initials: J
authors.lastname: Ravits
authors.affiliation: Ludwig Institute for Cancer Research, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0670, USA. dcleveland@ucsd.edu.|Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0670, USA. dcleveland@ucsd.edu.|Department of Neurosciences, University of California, San Diego, La Jolla, CA, 92093, USA. dcleveland@ucsd.edu.
authors.forename: Don W
authors.initials: DW
authors.lastname: Cleveland
authors.affiliation: Ludwig Institute for Cancer Research, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0670, USA. sdacruz@ucsd.edu.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Da Cruz
mesh_terms: D000328:Adult; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism / Q000473:pathology; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D009043:Motor Activity / Q000502:physiology; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D009469:Neuromuscular Junction / Q000378:metabolism / Q000473:pathology; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; C000598624:TARDBP protein, human
keywords: Amyotrophic lateral sclerosis (ALS); Frontotemporal dementia (FTD); Motor neuron; Mouse model; Neurodegeneration; Non-cell autonomous; RanGAP1; TDP-43