title: Partial loss of TDP-43 function causes phenotypes of amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease that causes motor neuron degeneration, progressive motor dysfunction, paralysis, and death. Although multiple causes have been identified for this disease, >95% of ALS cases show aggregation of transactive response DNA binding protein (TDP-43) accompanied by its nuclear depletion. Therefore, the TDP-43 pathology may be a converging point in the pathogenesis that originates from various initial triggers. The aggregation is thought to result from TDP-43 misfolding, which could generate cellular toxicity. However, the aggregation as well as the nuclear depletion could also lead to a partial loss of TDP-43 function or TDP-43 dysfunction. To investigate the impact of TDP-43 dysfunction, we generated a transgenic mouse model for a partial loss of TDP-43 function using transgenic RNAi. These mice show ubiquitous transgene expression and TDP-43 knockdown in both the periphery and the central nervous system (CNS). Strikingly, these mice develop progressive neurodegeneration prominently in cortical layer V and spinal ventral horn, motor dysfunction, paralysis, and death. Furthermore, examination of splicing patterns of TDP-43 target genes in human ALS revealed changes consistent with TDP-43 dysfunction. These results suggest that the CNS, particularly motor neurons, possess a heightened vulnerability to TDP-43 dysfunction. Additionally, because TDP-43 knockdown predominantly occur in astrocytes in the spinal cord of these mice, our results suggest that TDP-43 dysfunction in astrocytes is an important driver for motor neuron degeneration and clinical phenotypes of ALS.
authors.affiliation: Departments of Biochemistry and Molecular Pharmacology, Neurology, Pathology, and Cell Biology, RNA Therapeutic Institute, Howard Hughes Medical Institute, and Neuroscience Program, University of Massachusetts Medical School, Worcester, MA 01605.
authors.forename: Chunxing
authors.initials: C
authors.lastname: Yang
authors.forename: Hongyan
authors.initials: H
authors.lastname: Wang
authors.forename: Tao
authors.initials: T
authors.lastname: Qiao
authors.forename: Bin
authors.initials: B
authors.lastname: Yang
authors.forename: Leonardo
authors.initials: L
authors.lastname: Aliaga
authors.forename: Linghua
authors.initials: L
authors.lastname: Qiu
authors.forename: Weijia
authors.initials: W
authors.lastname: Tan
authors.forename: Johnny
authors.initials: J
authors.lastname: Salameh
authors.forename: Diane M
authors.initials: DM
authors.lastname: McKenna-Yasek
authors.forename: Thomas
authors.initials: T
authors.lastname: Smith
authors.forename: Lingtao
authors.initials: L
authors.lastname: Peng
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Moore
authors.forename: Robert H
authors.initials: RH
authors.lastname: Brown
authors.forename: Huaibin
authors.initials: H
authors.lastname: Cai
authors.forename: Zuoshang
authors.initials: Z
authors.lastname: Xu
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000503:physiopathology*; D000818:Animals; D030801:Animals, Genetically Modified; D002490:Central Nervous System / Q000503:physiopathology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D051379:Mice; D010641:Phenotype
chemical_list: D004268:DNA-Binding Proteins; C578077:Tardbp protein, mouse
keywords: FTD; FTLD; Lou Gehrig's disease; neurodegenerative disease; noncell autonomous toxicity