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Author Notes:

Yunbo Liu: yunboliu@126.com

Or Shihua Li: sli@emory.edu

Or Xiao-Jiang Li xli2@emory.ed

X-JL, PY and SL designed the experiments.

PY, XYG, WLY, S YAN, SY, TZ, QS performed experiments and analyzed data.

YBL provided the monkey facility.

PY and X-JL wrote the paper.

We thank the Emory University Viral Core Facility for generating AAV viruses; and Jinquan Gao, Hua Zhu, Qin Li, Haiquan Shang, Chong Xiao, and Xishan Ma for monkey surgery, animal care, and behavioral analysis.

Subjects:

Research Funding:

This work was supported by The National Key Research and Development Program of China (2017YFA0105102, 2017YFA0105201, 2016YFC1300500-2); GuangDong Province Science and Technology plan project (2018B030337001, 2017B020231001, 2015A020212027); and The National Natural Science Foundation of China (31500826, 91649115).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Clinical Neurology
  • Neurosciences
  • Pathology
  • Neurosciences & Neurology
  • TDP-43
  • Caspase-4
  • Non-human primate
  • Aggregation
  • Neurodegeneration
  • AMYOTROPHIC-LATERAL-SCLEROSIS
  • FRONTOTEMPORAL LOBAR DEGENERATION
  • ENDOPLASMIC-RETICULUM STRESS
  • INDUCED APOPTOSIS
  • REPEAT EXPANSION
  • MOTOR-NEURONS
  • ALS
  • MUTATIONS
  • CLEAVAGE
  • TARDBP

Caspase-4 mediates cytoplasmic accumulation of TDP-43 in the primate brains

Tools:

Journal Title:

Acta Neuropathologica

Volume:

Volume 137, Number 6

Publisher:

, Pages 919-937

Type of Work:

Article | Final Publisher PDF

Abstract:

The cytoplasmic accumulation of the nuclear TAR DNA-binding protein 43 (TDP-43) is a pathologic hallmark in amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and other neurological disorders. However, most transgenic TDP-43 rodent models show predominant nuclear distribution of TDP-43 in the brain. By expressing mutant TDP-43 (M337V) in the brains of rhesus monkeys and mice, we verified that mutant TDP-43 is distributed in the cytoplasm of the monkey brain and that the majority of mutant TDP-43 remains in the nuclei of the mouse brain. The primate-specific caspase-4, but not mouse homologue caspase-11, could remove the NLS-containing N-terminal domain and generate fragmented TDP-43 that accumulates in the cytoplasm. Moreover, increased expression of caspase-4 in the monkey brain promotes the cytoplasmic accumulation of endogenous TDP-43, and suppressing caspase-4 reduces the cytoplasmic distribution of endogenous TDP-43 in cultured human neural cells. Our findings suggest that primate-specific caspase-4-mediated cleavage of TDP-43 accounts for its cytoplasmic mislocalization in the primate brains and may serve as a potential therapeutic target.

Copyright information:

© 2019, The Author(s).

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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