title: TDP-43 neurotoxicity and protein aggregation modulated by heat shock factor and insulin/IGF-1 signaling.
abstract: TAR DNA-binding protein 43 (TDP-43) plays a key role in the neurodegenerative diseases including amyotrophic lateral sclerosis and frontotemporal lobar degeneration. The nature of the TDP-43-mediated neurotoxicity associated with these diseases is not yet understood. Here, we have established transgenic Caenorhabditis elegans models that express human TDP-43 variants in the nervous system, including the full-length wild-type (WT) and mutant proteins and a pathologic C-terminal fragment. The C. elegans models developed severe locomotor defects associated with the aggregation of TDP-43 in neurons. In comparison to parallel Cu/Zn superoxide dismutase worm models, transgenic full-length TDP-43, including the WT protein, was highly neurotoxic. In addition, TDP-43 demonstrated an unusually high tendency to aggregate, a property intrinsic to the WT protein. The C-terminal 25 kDa fragment of TDP-43 was unstable but remarkably aggregation-prone. Distinct disulfide-linked TDP-43 dimers and oligomers were detected. In C. elegans, the neurotoxicity and the protein aggregation of TDP-43 were regulated by environmental temperature and heat shock transcriptional factor 1, indicating that a deficiency in protein quality control is a risk factor for TDP-43 proteinopathy. Furthermore, the neurotoxicity and the protein aggregation of TDP-43 can be significantly attenuated by a deficiency in the insulin/insulin-like growth factor 1 (IGF-1) signaling in C. elegans and mammalian cells. These results suggest that protein misfolding underlies the aging-dependent neurodegeneration associated with TDP-43 and that the insulin/IGF-1 signaling may be a target for therapies.
authors.affiliation: Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Mullane
authors.forename: Goran
authors.initials: G
authors.lastname: Periz
authors.forename: Jiou
authors.initials: J
authors.lastname: Wang
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D000076249:Heat Shock Transcription Factors; D018869:Heat-Shock Response; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D042541:Intracellular Space / Q000378:metabolism; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D055503:Protein Multimerization; D021381:Protein Transport; D015398:Signal Transduction; D057177:TDP-43 Proteinopathies / Q000503:physiopathology; D013696:Temperature; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; D007328:Insulin; D014157:Transcription Factors; D007334:Insulin-Like Growth Factor I