Biomolecular condensates and disease pathogenesis

doi:10.1007/s11427-024-2661-3

Review

. 2024 Sep;67(9):1792-1832.

doi: 10.1007/s11427-024-2661-3. Epub 2024 Jul 17.

Biomolecular condensates and disease pathogenesis

Ke Ruan¹, Ge Bai^{2

3}, Yanshan Fang^{4

5}, Dan Li⁶, Tingting Li⁷, Xingguo Liu^{8

9}, Boxun Lu¹⁰, Qing Lu¹¹, Zhou Songyang¹², Shuguo Sun¹³, Zheng Wang¹⁴, Xin Zhang¹⁵, Wen Zhou¹⁶, Hong Zhang^{17

18}

Affiliations

¹ The First Affiliated Hospital & School of Life Sciences, Ministry of Education Key Laboratory for Membrane-less Organelles & Cellular Dynamics, Hefei National Research Center for Interdisciplinary Sciences at the Microscale, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China. kruan@ustc.edu.cn.
² Nanhu Brain-computer Interface Institute, Hangzhou, 311100, China. gebai@zju.edu.cn.
³ Department of Neurology of Second Affiliated Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China. gebai@zju.edu.cn.
⁴ Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 201210, China. fangys@sioc.ac.cn.
⁵ University of Chinese Academy of Sciences, Beijing, 100049, China. fangys@sioc.ac.cn.
⁶ Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, 200030, China. lidan2017@sjtu.edu.cn.
⁷ Department of Biomedical Informatics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China. litt@hsc.pku.edu.cn.
⁸ CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China. liu_xingguo@gibh.ac.cn.
⁹ Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, 510000, China. liu_xingguo@gibh.ac.cn.
¹⁰ Neurology Department at Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, School of Life Sciences, Fudan University, Shanghai, 200433, China. luboxun@fudan.edu.cn.
¹¹ Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, 200030, China. luqing67@sjtu.edu.cn.
¹² State Key Laboratory of Biocontrol, MOE Key Laboratory of Gene Function and Regulation and Guangzhou Key Laboratory of Healthy Aging Research, School of Life Sciences, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510275, China. songyanz@mail.sysu.edu.cn.
¹³ Department of Human Anatomy, Histology and Embryology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. shuguo@hust.edu.cn.
¹⁴ The Second Affiliated Hospital, School of Basic Medical Sciences, Institute of Biomedical Innovation, Jiangxi Medical College, Nanchang University, Nanchang, 330031, China. wz1103@ncu.edu.cn.
¹⁵ Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, 310024, China. zhangxin@westlake.edu.cn.
¹⁶ Department of Immunology and Microbiology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, 518055, China. zhouw@sustech.edu.cn.
¹⁷ National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China. hongzhang@ibp.ac.cn.
¹⁸ College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China. hongzhang@ibp.ac.cn.

PMID: 39037698
DOI: 10.1007/s11427-024-2661-3

Review

Biomolecular condensates and disease pathogenesis

Ke Ruan et al. Sci China Life Sci. 2024 Sep.

. 2024 Sep;67(9):1792-1832.

doi: 10.1007/s11427-024-2661-3. Epub 2024 Jul 17.

Authors

Affiliations

¹ The First Affiliated Hospital & School of Life Sciences, Ministry of Education Key Laboratory for Membrane-less Organelles & Cellular Dynamics, Hefei National Research Center for Interdisciplinary Sciences at the Microscale, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027, China. kruan@ustc.edu.cn.
² Nanhu Brain-computer Interface Institute, Hangzhou, 311100, China. gebai@zju.edu.cn.
³ Department of Neurology of Second Affiliated Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China. gebai@zju.edu.cn.
⁴ Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 201210, China. fangys@sioc.ac.cn.
⁵ University of Chinese Academy of Sciences, Beijing, 100049, China. fangys@sioc.ac.cn.
⁶ Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, 200030, China. lidan2017@sjtu.edu.cn.
⁷ Department of Biomedical Informatics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China. litt@hsc.pku.edu.cn.
⁸ CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China. liu_xingguo@gibh.ac.cn.
⁹ Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, 510000, China. liu_xingguo@gibh.ac.cn.
¹⁰ Neurology Department at Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, School of Life Sciences, Fudan University, Shanghai, 200433, China. luboxun@fudan.edu.cn.
¹¹ Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, 200030, China. luqing67@sjtu.edu.cn.
¹² State Key Laboratory of Biocontrol, MOE Key Laboratory of Gene Function and Regulation and Guangzhou Key Laboratory of Healthy Aging Research, School of Life Sciences, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510275, China. songyanz@mail.sysu.edu.cn.
¹³ Department of Human Anatomy, Histology and Embryology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. shuguo@hust.edu.cn.
¹⁴ The Second Affiliated Hospital, School of Basic Medical Sciences, Institute of Biomedical Innovation, Jiangxi Medical College, Nanchang University, Nanchang, 330031, China. wz1103@ncu.edu.cn.
¹⁵ Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, 310024, China. zhangxin@westlake.edu.cn.
¹⁶ Department of Immunology and Microbiology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, 518055, China. zhouw@sustech.edu.cn.
¹⁷ National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China. hongzhang@ibp.ac.cn.
¹⁸ College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China. hongzhang@ibp.ac.cn.

PMID: 39037698
DOI: 10.1007/s11427-024-2661-3

Abstract

Biomolecular condensates or membraneless organelles (MLOs) formed by liquid-liquid phase separation (LLPS) divide intracellular spaces into discrete compartments for specific functions. Dysregulation of LLPS or aberrant phase transition that disturbs the formation or material states of MLOs is closely correlated with neurodegeneration, tumorigenesis, and many other pathological processes. Herein, we summarize the recent progress in development of methods to monitor phase separation and we discuss the biogenesis and function of MLOs formed through phase separation. We then present emerging proof-of-concept examples regarding the disruption of phase separation homeostasis in a diverse array of clinical conditions including neurodegenerative disorders, hearing loss, cancers, and immunological diseases. Finally, we describe the emerging discovery of chemical modulators of phase separation.

Keywords: biomolecular condensate; liquid-liquid phase separation; membraneless organelle.

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References

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[1] Abbasi, Z., Jafari Khamirani, H., Tabei, S.M.B., Manoochehri, J., Dianatpour, M., and Dastgheib, S.A. (2023). EPS8 variant causes deafness, autosomal recessive 102 (DFNB102) and literature review. Hum Genome Var 10, 1. - PubMed - PMC - DOI

[2] Abbasi, Z., Jafari Khamirani, H., Tabei, S.M.B., Manoochehri, J., Dianatpour, M., and Dastgheib, S.A. (2023). EPS8 variant causes deafness, autosomal recessive 102 (DFNB102) and literature review. Hum Genome Var 10, 1. - PubMed - PMC - DOI

[3] Abeliovich, A., Schmitz, Y., Fariñas, I., Choi-Lundberg, D., Ho, W.H., Castillo, P.E., Shinsky, N., Verdugo, J.M.G., Armanini, M., Ryan, A., et al. (2000). Mice lacking α-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25, 239–252. - PubMed - DOI

[4] Abeliovich, A., Schmitz, Y., Fariñas, I., Choi-Lundberg, D., Ho, W.H., Castillo, P.E., Shinsky, N., Verdugo, J.M.G., Armanini, M., Ryan, A., et al. (2000). Mice lacking α-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25, 239–252. - PubMed - DOI

[5] Ablasser, A., and Chen, Z.J. (2019). cGAS in action: Expanding roles in immunity and inflammation. Science 363, eaat8657. - PubMed - DOI

[6] Ablasser, A., and Chen, Z.J. (2019). cGAS in action: Expanding roles in immunity and inflammation. Science 363, eaat8657. - PubMed - DOI

[7] Ado, G., Noda, N., Vu, H.T., Perron, A., Mahapatra, A.D., Arista, K.P., Yoshimura, H., Packwood, D.M., Ishidate, F., Sato, S., et al. (2022). Discovery of a phase-separating small molecule that selectively sequesters tubulin in cells. Chem Sci 13, 5760–5766. - PubMed - PMC - DOI

[8] Ado, G., Noda, N., Vu, H.T., Perron, A., Mahapatra, A.D., Arista, K.P., Yoshimura, H., Packwood, D.M., Ishidate, F., Sato, S., et al. (2022). Discovery of a phase-separating small molecule that selectively sequesters tubulin in cells. Chem Sci 13, 5760–5766. - PubMed - PMC - DOI

[9] Agarwal, A., Arora, L., Rai, S.K., Avni, A., and Mukhopadhyay, S. (2022). Spatiotemporal modulations in heterotypic condensates of prion and α-synuclein control phase transitions and amyloid conversion. Nat Commun 13, 1154. - PubMed - PMC - DOI

[10] Agarwal, A., Arora, L., Rai, S.K., Avni, A., and Mukhopadhyay, S. (2022). Spatiotemporal modulations in heterotypic condensates of prion and α-synuclein control phase transitions and amyloid conversion. Nat Commun 13, 1154. - PubMed - PMC - DOI

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Biomolecular condensates and disease pathogenesis

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