Cell Research Li Dan/Wang Jian/Liu Cong collaborated to discover and characterize novel pathological protein fibril aggregates formed by TMEM106B in the human brain

Protein fiber aggregates formed by pathological proteins through liquid-solid phase transition are important pathological markers of various neurodegenerative diseases (NDs)
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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
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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
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On April 27, 2022, Li Dan's research group from Shanghai Jiao Tong University, Wang Jian's research group from Huashan Hospital Affiliated to Fudan University, and Liu Cong's research group from the Interdisciplinary Center of Shanghai Institute of Organic Chemistry jointly published the title Generic amyloid fibrillation of TMEM106B in patient with Cell Research online.
Research results of Parkinson's disease dementia and normal elders
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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
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This work discovered a new class of pathological protein fibril aggregates in the brains of ND patients and healthy elderly people, and discussed the role of the newly discovered protein aggregates in NDs and aging
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Li Dan and Liu Cong's research group have cooperated for a long time to study the molecular mechanism of liquid-solid phase transition and aggregation of α-syn, a key protein in Parkinson's disease, and develop new methods for chemical intervention
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Previous studies were mainly carried out with the help of α-syn protein aggregates prepared in vitro (see BioArt report: Nat Commun | Liu Cong's group explained the molecular mechanism of α-syn pathological aggregation in familial Parkinson's disease; Nat Chem Biol's point of view | Cong Liu/Dan Li summarizes the key role of multi-level chemical regulation in the aggregation of pathogenic proteins in neurodegenerative diseases)
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In this work, the two research groups worked closely with Wang Jian's research group from Huashan Hospital to try to directly extract α-syn pathological protein aggregates from the brain tissue of PDD patients, and successfully extract protein fibers from the brain tissue through multi-step purification.
aggregates (Figure 1)
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Surprisingly, however, protein fibril aggregates extracted from PDD brain tissue were not formed by α-syn
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Further, the researchers identified this brand-new protein aggregate by cryo-electron microscopy and mass spectrometry and other techniques
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Figure 1.
Extraction method and results of protein fibril aggregates in human brain tissue
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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
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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 fiber aggregates with a similar β-sheet structure
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However, TMEM106B has subtle differences in the three different sources of fiber 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
.

It is worth mentioning that in the past month or so, Fitzpatrick's group at Columbia University, Eisenberg's group at UCLA, and Goedert & Scheres' group at Cambridge University have successively reported research results that are highly relevant to this study in Cell and Nature.
【1-3】
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Among them, the research group of Fitzpatrick and Eisenberg obtained TMEM106B pathological fiber aggregates from the brains of patients with different types of NDs (including frontotemporal lobar degeneration, progressive supranuclear palsy, dementia with Lewy bodies, etc.
), and believed that the aggregates formed by TMEM106B It is closely related to the pathogenesis of different NDs (especially frontotemporal lobar degeneration)
.

However, the Goedert & Scheres research group found that TMEM106B exists not only in the brain tissue of ND patients, but also in the brain tissue of elderly healthy people, and speculated that the TMEM106B aggregate may be an aging-related age-dependent protein aggregate, which is not directly related to the pathogenesis of ND.
association
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Therefore, 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
.

Accordingly, disease and age together are proposed as two key drivers for the formation of pathological fibrous aggregates in TMEM106B
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In conclusion, this research work unexpectedly discovered a new class of pathological fibrous aggregates formed by TMEM106B protein in the midbrain tissue of PDD patients and aged healthy controls
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And discuss the direct relationship between the formation of TMEM106B fibers and disease and aging
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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
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Fan Yun, a graduate student from Huashan Hospital Affiliated to Fudan University, Zhao Qinyue, a graduate student from Shanghai Jiao Tong University, and Xia Wencheng, a graduate student from the Interdisciplinary Center of the Shanghai Institute of Organic Chemistry are the co-first authors of the paper
.

Link to the original text: https:// In addition: Postdoctoral and Technician Recruitment for Li Dan's research group at Shanghai Jiao Tong University and Liu Cong's research group at the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences Hire outstanding talents (including postdoctoral fellows and technicians) to join the team to explore the pathological mechanism of protein phase transition and pathological aggregation in neurodegenerative diseases, and develop small molecule-based chemical interventions and diseases through the cross-research paradigm of chemistry-biology-medicine New strategies for early clinical diagnosis
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The research team will provide good scientific research development opportunities and superior treatment
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The research group of Wang Jian from Huashan Hospital Affiliated to Fudan University is looking for a super postdoctoral fellow from Fudan University to join the team to conduct clinical and basic research on neuroimaging, pathogenesis, early diagnosis and modified treatment of Parkinson's disease and related neurodegenerative diseases
.

The research group will provide good opportunities for scientific research and development and favorable treatment
.

Resume delivery (if you are interested, please send your resume and other materials to): https://jinshuju.
net/f/ZqXwZt or scan the QR code to send your resume dependent formation of TMEM106B amyloid filaments in human brains.
Nature, doi:10.
1038/s41586-022-04650-z (2022).
2 Chang, A.
et al.
Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases.
Cell, doi:10.
1016/ j.
cell.
2022.
02.
026 (2022).
3 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) .
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