TY - JOUR
T1 - TDP-43 neurotoxicity and protein aggregation modulated by heat shock factor and insulin/IGF-1 signaling
AU - Zhang, Tao
AU - Mullane, Patrick C.
AU - Periz, Goran
AU - Wang, Jiou
N1 - Funding Information:
This work was supported by the National Institutes of Health (NS062089) to J.W., the Robert Packard Center for ALS Research at Johns Hopkins, the Muscular Dystrophy Association and the Johns Hopkins Claude D. Pepper Older Americans Independence Center.
Funding Information:
We would like to thank Katherine H. Reiter for her technical assistance and Wang laboratory members for helpful discussion. We thank Dr David Borchelt for reading the manuscript. Some nematode strains used in this work were provided by Caenorhabditis Genetics Center, an NIH supported National Center for Research Resources.
PY - 2011/5
Y1 - 2011/5
N2 - TARDNA-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, wehave 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 theWTprotein. The C-terminal 25 kDa fragment of TDP-43 was unstable but remarkably aggregation-prone. Distinct disulfidelinked 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.
AB - TARDNA-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, wehave 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 theWTprotein. The C-terminal 25 kDa fragment of TDP-43 was unstable but remarkably aggregation-prone. Distinct disulfidelinked 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.
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U2 - 10.1093/hmg/ddr076
DO - 10.1093/hmg/ddr076
M3 - Article
C2 - 21355045
AN - SCOPUS:79955433159
SN - 0964-6906
VL - 20
SP - 1952
EP - 1965
JO - Human molecular genetics
JF - Human molecular genetics
IS - 10
M1 - ddr076
ER -