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Author Notes:

Correspondence: sli@emory.edu (SL); xli2@emory.edu (XJL)

Conceived and designed the experiments: XL XJL SL.

Performed the experiments: XL CEW YH TZ GW MS SL.

Analyzed the data: XL CEW SL XJL.

Contributed reagents/materials/analysis tools: MAG.

Wrote the paper: XL SL XJL.

We thank Meredith Roberts for technical assistance, Dr. Scott Zeitlin at University of Virginia for providing floxed Htt KO mice, Heju Zhang at the Transgenic Mouse/Gene Targeting Core Facility at Emory University for generating transgenic mice, Dr. Nicole Déglon for providing huntingtin shRNA vectors, and Cheryl Strauss for critical reading of this manuscript.

The authors have declared that no competing interests exist.

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.


Research Funding:

This work was supported by grants from the National Institutes of Health (NS041449, AG019206) XJL, (NS095279) SL, and the National Key Basic Research Program of China (2012CBA01304), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB13000000), and the State Key Laboratory of Molecular Developmental Biology, China.


  • Neurons
  • Mouse models
  • Neostriatum
  • Neurites
  • Astrocytes
  • Phenotypes
  • Huntington disease
  • Embryos

N-terminal Huntingtin Knock-In Mice: Implications of Removing the N-terminal Region of Huntingtin for Therapy


Journal Title:

PLoS Genetics


Volume 12, Number 5


, Pages e1006083-e1006083

Type of Work:

Article | Final Publisher PDF


The Huntington’s disease (HD) protein, huntingtin (HTT), is a large protein consisting of 3144 amino acids and has conserved N-terminal sequences that are followed by a polyglutamine (polyQ) repeat. Loss of Htt is known to cause embryonic lethality in mice, whereas polyQ expansion leads to adult neuronal degeneration. Whether N-terminal HTT is essential for neuronal development or contributes only to late-onset neurodegeneration remains unknown. We established HTT knock-in mice (N160Q-KI) expressing the first 208 amino acids of HTT with 160Q, and they show age-dependent HTT aggregates in the brain and neurological phenotypes. Importantly, the N-terminal mutant HTT also preferentially accumulates in the striatum, the brain region most affected in HD, indicating the importance of N-terminal HTT in selective neuropathology. That said, homozygous N160Q-KI mice are also embryonic lethal, suggesting that N-terminal HTT alone is unable to support embryonic development. Using Htt knockout neurons, we found that loss of Htt selectively affects the survival of developing neuronal cells, but not astrocytes, in culture. This neuronal degeneration could be rescued by a truncated HTT lacking the first 237 amino acids, but not by N-terminal HTT (1–208 amino acids). Also, the rescue effect depends on the region in HTT known to be involved in intracellular trafficking. Thus, the N-terminal HTT region may not be essential for the survival of developing neurons, but when carrying a large polyQ repeat, can cause selective neuropathology. These findings imply a possible therapeutic benefit of removing the N-terminal region of HTT containing the polyQ repeat to treat the neurodegeneration in HD.

Copyright information:

© 2016 Liu et al.

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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