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    Home > Biochemistry News > Biotechnology News > Shanghai Jiaotong University Li Dan's group and collaborators discovered and characterized a novel pathological protein fiber aggregate formed by TMEM106B in the human brain

    Shanghai Jiaotong University Li Dan's group and collaborators discovered and characterized a novel pathological protein fiber aggregate formed by TMEM106B in the human brain

    • Last Update: 2022-05-10
    • Source: Internet
    • Author: User
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    Pathological protein fibrous aggregates formed by pathological proteins through liquid-solid phase transition are important pathological markers of various neurodegenerative diseases (NDs)
    .
    Pathological aggregates formed by different proteins have been found in different NDs with various pathological toxicities, including activation of neuroinflammation, disruption of protein homeostasis, induction of mitochondrial damage, and spread across brain regions and organs

    .
    Therefore, the study of the structure, aggregation mechanism and pathological toxicity of pathological protein aggregates is of great significance for understanding the pathogenic mechanism of NDs and drug development

    .

    On April 27, 2022, Li Dan's research group, associate professor appointed by the Dean of Bio-X Research of Shanghai Jiao Tong University, cooperated with Wang Jian's research group of Huashan Hospital Affiliated to Fudan University, and Liu Cong's research group of Shanghai Institute of Organic Chemistry Interdisciplinary Research Center in Cell Research .
    Published online research results titled "Generic amyloid fibrillation of TMEM106B in patient with Parkinson's disease dementia and normal elders"

    .
    In this study, researchers discovered a previously unknown cluster of novel pathological proteins extracted directly from the brain tissue of a Parkinson's disease dementia (PDD) patient with dementia and two elderly healthy controls.
    Furthermore, cryo-electron microscopy and mass spectrometry revealed that this new protein pathological aggregate was formed by the transmembrane protein 106B (transmembrane protein 106B, TMEM106B) folded into a novel curling sheet structural unit and further self-assembled

    .
    This work discovered a new class of pathological protein fibril aggregates coexisting in the brains of ND patients and healthy elderly, and discussed the role of the newly discovered protein aggregates in NDs and aging

    .

    Li Dan's group has long been devoted to studying the molecular mechanism of the liquid-solid phase transition and aggregation of α-synuclein (α-syn), a key protein in Parkinson's disease, and developing new methods for chemical intervention and tracing
    .
    By developing three-dimensional helical reconstruction techniques including cryo-electron microscopy and electron diffraction techniques, we have systematically studied and found that different internal and external conditions can induce α-syn to form pathological protein aggregates with different three-dimensional structures through liquid-solid phase transition

    .
    However, previous studies were mainly based on α-syn protein aggregates prepared in vitro

    .
    In this work, Li Dan's research group worked closely with collaborators to directly extract α-syn pathological protein aggregates from the brain tissue of PDD patients for the first time, and finally successfully extracted protein fiber aggregates from brain tissue through multi-step purification ( Figure 1)

    .
    Surprisingly, however, protein fibril aggregates extracted from PDD brain tissue were not formed by α-syn

    .
    Further, the researchers identified this brand-new protein aggregate by cryo-electron microscopy and mass spectrometry and other techniques

    .

    Figure 1.
    Extraction method and results of protein fiber aggregates in human brain tissue

    More interestingly, in addition to the brain tissue of PDD patients, the researchers also obtained the same protein fiber aggregates formed by TMEM106B from the brain tissue of two other elderly healthy controls
    .
    Further studies found that TMEM106B formed a novel curling conformation different from its native conformation in PDD and two healthy control brain tissues and assembled into fibrous aggregates with a β-sheet structure

    .
    However, there were subtle differences in the local conformation of TMEM106B among the three different fibrous aggregates

    .
    In healthy control No.
    2, TMEM106B presented a Type 1 structure composed of single-strand fibrils (Fig.
    2); in healthy control No.
    1, it was a Type 2 structure composed of single-strand fibrils; in PDD, TMEM106B with both structures coexisted Fibers, one with the same Type 1 structure as the healthy control No.
    1, and the other with the Type 3 structure consisting of two fibrils with the same structure as Type 1

    .
    Both Type 1 and Type 2 fiber aggregates consisted of the C-terminal domain (Residue 120–254) of TEME106B, forming a curling-like configuration containing 17 β-sheets (Fig.
    2)

    .


    Figure 2.
    Cryo-EM structure of TMEM106B fiber aggregates in brain tissue of PDD patients and aged healthy controls

    It is worth mentioning that Cao Li, an associate professor of our dean's teaching track, recently published a similar discovery in Nature1 (https://mp.
    weixin.
    qq.
    com/s/XvdcLufikKw-U3oeSBi5MQ)

    .
    In the past month or so, the Fitzpatrick research group of Columbia University and the Goedert & Scheres research group of Cambridge University have also successively reported related research results in Cell and Nature 2, 3

    .
    However, the above three works have great controversy on the pathological significance of TMEM106B fibrous aggregates

    .
    In this work, the researchers comprehensively analyzed the age distribution characteristics of brain tissue donors used to extract TMEM106B fiber aggregates reported in this work and the above three works in different subgroups, and found that whether familial or sporadic The age of NDs patients was significantly lower than that of healthy controls (Fig.
    3)

    .
    Accordingly, disease and age together are proposed as two key drivers for the formation of pathological fibrous aggregates in TMEM106B

    .

     

    Figure 3.
    Statistical analysis of age of brain tissue donors containing TMEM106B fibers 

    In conclusion, this study unexpectedly discovered a new type of pathological fibrous aggregates formed by TMEM106B protein from the midbrain tissue of PDD patients and aged healthy controls, and discussed the direct relationship between the formation of TMEM106B fibers and disease and aging
    .
    This work provides new insights for understanding the complex role of different protein pathological aggregates in disease and aging; it opens up new ideas for further exploring the complex pathological and physiological activities of different protein aggregates in the human brain; This presents new challenges for the development of PET tracers that identify pathological protein aggregates

    .

    Zhao Qinyue, a graduate student of the Bio-X Research Institute of Shanghai Jiao Tong University, is the co-first author of the paper.
    The other two first authors are Fan Yun, a graduate student of Huashan Hospital affiliated to Fudan University, and Xia Wencheng, a graduate student of the Interdisciplinary Research Center of Biology and Chemistry, Shanghai Institute of Organic Chemistry

    .
    The cooperative units of the paper are Shanghai Jiaotong University, Huashan Hospital Affiliated to Fudan University, and the Interdisciplinary Research Center of Biology and Chemistry of Shanghai Institute of Organic Chemistry

    .

    Article link: https://#Sec1

    references:

    1.
    Jiang, YX et al.
    Amyloid fibrils in disease FTLD-TDP are composed of TMEM106B not TDP-43.
    Nature, doi:10.
    1038/s41586-022-04670-9 (2022).

    2.
    Chang, A.
    et al.
    Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases.
    Cell 185, 1346-1355.
    e1315, doi:10.
    1016/j.
    cell.
    2022.
    02.
    026 (2022).

    3.
    Schweighauser, M.
    et al.
    Age-dependent formation of TMEM106B amyloid filaments in human brains.
    Nature, doi:10.
    1038/s41586-022-04650-z (2022).





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    Bio-X Research Institute



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