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Mutant TDP-43 within motor neurons drives disease onset but not progression in amyotrophic lateral sclerosis

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-causi...

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Detalles Bibliográficos
Autores principales: Ditsworth, Dara, Maldonado, Marcus, McAlonis-Downes, Melissa, Sun, Shuying, Seelman, Amanda, Drenner, Kevin, Arnold, Eveline, Ling, Shuo-Chien, Pizzo, Donald, Ravits, John, Cleveland, Don W., Da Cruz, Sandrine
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5427168/
https://www.ncbi.nlm.nih.gov/pubmed/28357566
http://dx.doi.org/10.1007/s00401-017-1698-6
Descripción
Sumario: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-43(Q331K) mice develop age- and mutant-dependent motor deficits from degeneration and death of motor neurons. Cre-recombinase-mediated excision of the TDP-43(Q331K) 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00401-017-1698-6) contains supplementary material, which is available to authorized users.