Galectin-3 is required for the microglia-mediated brain inflammation in a model of Huntington’s disease

Jian Jing Siew; Hui Mei Chen; Huan Yuan Chen; Hung Lin Chen; Chiung Mei Chen; Bing Wen Soong; Yih Ru Wu; Ching Pang Chang; Yi Chen Chan; Chun Hung Lin; Fu Tong Liu; Yijuang Chern

doi:10.1038/s41467-019-11441-0

Galectin-3 is required for the microglia-mediated brain inflammation in a model of Huntington’s disease

Jian Jing Siew, Hui Mei Chen, Huan Yuan Chen, Hung Lin Chen, Chiung Mei Chen, Bing Wen Soong, Yih Ru Wu, Ching Pang Chang, Yi Chen Chan, Chun Hung Lin, Fu Tong Liu, Yijuang Chern

Taipei Medical University Shuang Ho Hospital

Research output: Contribution to journal › Article › peer-review

104 Citations (Scopus)

Abstract

Huntington’s disease (HD) is a neurodegenerative disorder that manifests with movement dysfunction. The expression of mutant Huntingtin (mHTT) disrupts the functions of brain cells. Galectin-3 (Gal3) is a lectin that has not been extensively explored in brain diseases. Herein, we showed that the plasma Gal3 levels of HD patients and mice correlated with disease severity. Moreover, brain Gal3 levels were higher in patients and mice with HD than those in controls. The up-regulation of Gal3 in HD mice occurred before motor impairment, and its level remained high in microglia throughout disease progression. The cell-autonomous up-regulated Gal3 formed puncta in damaged lysosomes and contributed to inflammation through NFκB- and NLRP3 inflammasome-dependent pathways. Knockdown of Gal3 suppressed inflammation, reduced mHTT aggregation, restored neuronal DARPP32 levels, ameliorated motor dysfunction, and increased survival in HD mice. Thus, suppression of Gal3 ameliorates microglia-mediated pathogenesis, which suggests that Gal3 is a novel druggable target for HD.

Original language	English
Article number	3473
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-11441-0
Publication status	Published - Dec 1 2019

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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title = "Galectin-3 is required for the microglia-mediated brain inflammation in a model of Huntington{\textquoteright}s disease",

abstract = "Huntington{\textquoteright}s disease (HD) is a neurodegenerative disorder that manifests with movement dysfunction. The expression of mutant Huntingtin (mHTT) disrupts the functions of brain cells. Galectin-3 (Gal3) is a lectin that has not been extensively explored in brain diseases. Herein, we showed that the plasma Gal3 levels of HD patients and mice correlated with disease severity. Moreover, brain Gal3 levels were higher in patients and mice with HD than those in controls. The up-regulation of Gal3 in HD mice occurred before motor impairment, and its level remained high in microglia throughout disease progression. The cell-autonomous up-regulated Gal3 formed puncta in damaged lysosomes and contributed to inflammation through NFκB- and NLRP3 inflammasome-dependent pathways. Knockdown of Gal3 suppressed inflammation, reduced mHTT aggregation, restored neuronal DARPP32 levels, ameliorated motor dysfunction, and increased survival in HD mice. Thus, suppression of Gal3 ameliorates microglia-mediated pathogenesis, which suggests that Gal3 is a novel druggable target for HD.",

author = "Siew, {Jian Jing} and Chen, {Hui Mei} and Chen, {Huan Yuan} and Chen, {Hung Lin} and Chen, {Chiung Mei} and Soong, {Bing Wen} and Wu, {Yih Ru} and Chang, {Ching Pang} and Chan, {Yi Chen} and Lin, {Chun Hung} and Liu, {Fu Tong} and Yijuang Chern",

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AU - Chen, Hui Mei

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AU - Chen, Hung Lin

AU - Chen, Chiung Mei

AU - Soong, Bing Wen

AU - Wu, Yih Ru

AU - Chang, Ching Pang

AU - Chan, Yi Chen

AU - Lin, Chun Hung

AU - Liu, Fu Tong

AU - Chern, Yijuang

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Huntington’s disease (HD) is a neurodegenerative disorder that manifests with movement dysfunction. The expression of mutant Huntingtin (mHTT) disrupts the functions of brain cells. Galectin-3 (Gal3) is a lectin that has not been extensively explored in brain diseases. Herein, we showed that the plasma Gal3 levels of HD patients and mice correlated with disease severity. Moreover, brain Gal3 levels were higher in patients and mice with HD than those in controls. The up-regulation of Gal3 in HD mice occurred before motor impairment, and its level remained high in microglia throughout disease progression. The cell-autonomous up-regulated Gal3 formed puncta in damaged lysosomes and contributed to inflammation through NFκB- and NLRP3 inflammasome-dependent pathways. Knockdown of Gal3 suppressed inflammation, reduced mHTT aggregation, restored neuronal DARPP32 levels, ameliorated motor dysfunction, and increased survival in HD mice. Thus, suppression of Gal3 ameliorates microglia-mediated pathogenesis, which suggests that Gal3 is a novel druggable target for HD.

AB - Huntington’s disease (HD) is a neurodegenerative disorder that manifests with movement dysfunction. The expression of mutant Huntingtin (mHTT) disrupts the functions of brain cells. Galectin-3 (Gal3) is a lectin that has not been extensively explored in brain diseases. Herein, we showed that the plasma Gal3 levels of HD patients and mice correlated with disease severity. Moreover, brain Gal3 levels were higher in patients and mice with HD than those in controls. The up-regulation of Gal3 in HD mice occurred before motor impairment, and its level remained high in microglia throughout disease progression. The cell-autonomous up-regulated Gal3 formed puncta in damaged lysosomes and contributed to inflammation through NFκB- and NLRP3 inflammasome-dependent pathways. Knockdown of Gal3 suppressed inflammation, reduced mHTT aggregation, restored neuronal DARPP32 levels, ameliorated motor dysfunction, and increased survival in HD mice. Thus, suppression of Gal3 ameliorates microglia-mediated pathogenesis, which suggests that Gal3 is a novel druggable target for HD.

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Galectin-3 is required for the microglia-mediated brain inflammation in a model of Huntington’s disease

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