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Differential expression and roles of Huntingtin and Huntingtin-associated protein 1 in the mouse and primate brains

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Abstract

Huntingtin-associated protein 1 (HAP1) is the first identified protein whose function is affected by its abnormal interaction with mutant huntingtin (mHTT), which causes Huntington disease. However, the expression patterns of Hap1 and Htt in the rodent brain are not correlated. Here we found that the primate HAP1, unlike the rodent Hap1, is correlatively expressed with HTT in the primate brains. CRISPR/Cas9 targeting revealed that HAP1 deficiency in the developing human neurons did not affect neuronal differentiation and gene expression as seen in the mouse neurons. However, deletion of HAP1 exacerbated neurotoxicity of mutant HTT in the organotypic brain slices of adult monkeys. These findings demonstrate differential HAP1 expression and function in the mouse and primate brains, and suggest that interaction of HAP1 with mutant HTT may be involved in mutant HTT-mediated neurotoxicity in adult primate neurons.

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Data availability

The raw data from this publication have been deposited. The RNA sequencing data that support the findings of this study are available in NCBI’s sequence read archive (SRA) database through Bioproject Accession number: PRJNA796166 (https://www.ncbi.nlm.nih.gov/bioproject/PRJNA796166/).

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Acknowledgements

We thank Professor Xiao-Xin Yan at Xiangya School of Medicine, Central South University, Changsha, China for providing human postmortem brain tissues, Yuefeng Li at Guangdong Landao Biotechnology Co. Ltd for animal care and experiment. This work was supported by The National Natural Science Foundation of China (81830032, 82071421, 31872779, 81901289), Guangzhou Key Research Program on Brain Science (202007030008), Department of Science and Technology of Guangdong Province (2021ZT09Y007; 2020B121201006; 2018B030337001). XC was funded by Science and Technology Research Project of Education Department of Hubei Province (B2020020). This study was supported by the high performance public computing service platform of Jinan University.

Funding

This research was funded by National Natural Science Foundation of China, Grant numbers [82071421, 81830032, 31872779].

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Authors and Affiliations

  1. Brain Science and Advanced Technology Institute, Wuhan University of Science and Technology, Wuhan, 430000, Hubei, China

    Xingxing Chen & Yan Zeng

  2. Guangdong Key Laboratory of Non-Human Primate Research, Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, 510632, China

    Xingxing Chen, Yize Sun, Laiqiang Chen, Xiu-sheng Chen, Mingtian Pan, Yiran Zhang, Qi Wang, Weili Yang, Peng Yin, Dajian He, Xiangyu Guo, Su Yang, Sen Yan, Xiao-Jiang Li & Shihua Li

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  1. Xingxing Chen
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Contributions

SL and X-JL designed experiments. XC performed all the experiments with the help of YS. LC performed RNA-seq data analysis. X-SC conducted monkey cortical neurons culture. MP conducted organotypic monkey brain slice culture. YZ and QW aided in molecular biological experiments. WY, PY, DH, XG, SY, YZ and S Yan provided important advice, reagents, and experimental samples. XC, X-J L and SL wrote the paper.

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Correspondence to Xiao-Jiang Li or Shihua Li.

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Chen, X., Sun, Y., Chen, L. et al. Differential expression and roles of Huntingtin and Huntingtin-associated protein 1 in the mouse and primate brains. Cell. Mol. Life Sci. 79, 554 (2022). https://doi.org/10.1007/s00018-022-04577-8

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