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Accumulation of Endogenous Mutant Huntingtin in Astrocytes Exacerbates Neuropathology of Huntington Disease in Mice

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Abstract

Selective neuronal accumulation of misfolded proteins is a key step toward neurodegeneration in a wide range of neurodegenerative diseases, including Huntington’s (HD) diseases. Our recent studies suggest that Hsp70-binding protein 1 (HspBP1), an Hsp70/CHIP inhibitor that reduces protein folding, is highly expressed in neuronal cells and accounts for the accumulation of the HD protein huntingtin (HTT) in neuronal cells. To further determine the role of HspBP1 in regulation of mutant protein accumulation, we investigated whether increasing expression of HspBP1 in glial cells can also induce the accumulation of endogenous mutant HTT in glial cells and yield non-cell-autonomous toxic effects. We performed stereotaxic injection of AAV to selectively express HspBP1 in astrocytes in the brains of HD140Q knock-in (KI) mice that express mutant HTT ubiquitously but do not display obvious neurodegeneration. However, HspBP1 expression in HD140Q astrocytes led to the increased accumulation of endogenous mutant HTT and robust neuronal loss in the striatum of HD140Q KI mice. In transgenic HD mice that selectively express mutant HTT in astrocytes, increased accumulation of mutant HTT in astrocytes via HspBP1 expression did not elicit neurodegeneration but could exacerbate neurological symptoms. Consistently, suppressing the expression of endogenous HspBp1 in the striatum of HD140Q KI mice via CRISPR/Cas9 led to a significant reduction of mutant HTT accumulation. Our findings suggest that although endogenous mutant HTT in astrocytes can exacerbate neurological symptoms, it mediates neurodegeneration only when mutant HTT is also accumulated in neuronal cells.

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Acknowledgements

We thank Jennifer Zhang for maintaining mouse lines and technical assistance.

Funding

This work is supported by the National Institutes of Health grants (R56 AG019206; R01NS101701), National Natural Science Foundation of China (81830032; 31872779; 32070534; 82071421), Guangzhou Key Research Program on Brain Science (202007030008), Key Field Research and Development Program of Guangdong province (2018B030337001), The National Key Research and Development Program of China, Stem Cell and Translational Research (2017YFA0105102).

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Authors and Affiliations

  1. Department of Emergency, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hunan, China

    Liang Jing

  2. Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, 30322, USA

    Liang Jing & Siying Cheng

  3. Key Laboratory of Hunan Province in Neurodegenerative Disorders, Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China

    Siying Cheng, Yongcheng Pan & Qiong Liu

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

    Weili Yang, Shihua Li & Xiao-Jiang Li

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Contributions

LJ, SL, and XL conceived and designed the experiments. LJ conducted most of experiments. SC, YP, QL, and WY provided technical assistance or performed part of experiments. LJ and XL wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Xiao-Jiang Li.

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All animal procedures were approved by the Institutional Animal Use and Care Committee at Emory University and carried out in accordance with the guidelines of Animal Use and Care of the National Institutes of Health (NIH).

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Jing, L., Cheng, S., Pan, Y. et al. Accumulation of Endogenous Mutant Huntingtin in Astrocytes Exacerbates Neuropathology of Huntington Disease in Mice. Mol Neurobiol 58, 5112–5126 (2021). https://doi.org/10.1007/s12035-021-02451-5

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