Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases

Andrew Chang; Xinyu Xiang; Jing Wang; Carolyn Lee; Tamta Arakhamia; Marija Simjanoska; Chi Wang; Yari Carlomagno; Guoan Zhang; Shikhar Dhingra; Manon Thierry; Jolien Perneel; Bavo Heeman; Lauren M. Forgrave; Michael DeTure; Mari L. DeMarco; Casey N. Cook; Rosa Rademakers; Dennis W. Dickson; Leonard Petrucelli; Michael H.B. Stowell; Ian R.A. Mackenzie; Anthony W.P. Fitzpatrick

doi:10.1016/j.cell.2022.02.026

Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases

Andrew Chang, Xinyu Xiang, Jing Wang, Carolyn Lee, Tamta Arakhamia, Marija Simjanoska, Chi Wang, Yari Carlomagno, Guoan Zhang, Shikhar Dhingra, Manon Thierry, Jolien Perneel, Bavo Heeman, Lauren M. Forgrave, Michael DeTure, Mari L. DeMarco, Casey N. Cook, Rosa Rademakers, Dennis W. Dickson, Leonard PetrucelliMichael H.B. Stowell, Ian R.A. Mackenzie, Anthony W.P. Fitzpatrick

Neuroscience

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

Abstract

Misfolding and aggregation of disease-specific proteins, resulting in the formation of filamentous cellular inclusions, is a hallmark of neurodegenerative disease with characteristic filament structures, or conformers, defining each proteinopathy. Here we show that a previously unsolved amyloid fibril composed of a 135 amino acid C-terminal fragment of TMEM106B is a common finding in distinct human neurodegenerative diseases, including cases characterized by abnormal aggregation of TDP-43, tau, or α-synuclein protein. A combination of cryoelectron microscopy and mass spectrometry was used to solve the structures of TMEM106B fibrils at a resolution of 2.7 Å from postmortem human brain tissue afflicted with frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP, n = 8), progressive supranuclear palsy (PSP, n = 2), or dementia with Lewy bodies (DLB, n = 1). The commonality of abundant amyloid fibrils composed of TMEM106B, a lysosomal/endosomal protein, to a broad range of debilitating human disorders indicates a shared fibrillization pathway that may initiate or accelerate neurodegeneration.

Original language	English (US)
Pages (from-to)	1346-1355.e15
Journal	Cell
Volume	185
Issue number	8
DOIs	https://doi.org/10.1016/j.cell.2022.02.026
State	Published - Apr 14 2022

Keywords

DLB
FTLD-TDP
PSP
TMEM106B
amyloid fibrils
cryo-EM
endosome
lysosome
neurodegeneration
proteolysis

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2022.02.026

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Chang, A., Xiang, X., Wang, J., Lee, C., Arakhamia, T., Simjanoska, M., Wang, C., Carlomagno, Y., Zhang, G., Dhingra, S., Thierry, M., Perneel, J., Heeman, B., Forgrave, L. M., DeTure, M., DeMarco, M. L., Cook, C. N., Rademakers, R., Dickson, D. W., ... Fitzpatrick, A. W. P. (2022). Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases. Cell, 185(8), 1346-1355.e15. https://doi.org/10.1016/j.cell.2022.02.026

Chang, A, Xiang, X, Wang, J, Lee, C, Arakhamia, T, Simjanoska, M, Wang, C, Carlomagno, Y, Zhang, G, Dhingra, S, Thierry, M, Perneel, J, Heeman, B, Forgrave, LM, DeTure, M, DeMarco, ML, Cook, CN, Rademakers, R, Dickson, DW , Petrucelli, L, Stowell, MHB, Mackenzie, IRA & Fitzpatrick, AWP 2022, 'Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases', Cell, vol. 185, no. 8, pp. 1346-1355.e15. https://doi.org/10.1016/j.cell.2022.02.026

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title = "Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases",

abstract = "Misfolding and aggregation of disease-specific proteins, resulting in the formation of filamentous cellular inclusions, is a hallmark of neurodegenerative disease with characteristic filament structures, or conformers, defining each proteinopathy. Here we show that a previously unsolved amyloid fibril composed of a 135 amino acid C-terminal fragment of TMEM106B is a common finding in distinct human neurodegenerative diseases, including cases characterized by abnormal aggregation of TDP-43, tau, or α-synuclein protein. A combination of cryoelectron microscopy and mass spectrometry was used to solve the structures of TMEM106B fibrils at a resolution of 2.7 {\AA} from postmortem human brain tissue afflicted with frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP, n = 8), progressive supranuclear palsy (PSP, n = 2), or dementia with Lewy bodies (DLB, n = 1). The commonality of abundant amyloid fibrils composed of TMEM106B, a lysosomal/endosomal protein, to a broad range of debilitating human disorders indicates a shared fibrillization pathway that may initiate or accelerate neurodegeneration.",

keywords = "DLB, FTLD-TDP, PSP, TMEM106B, amyloid fibrils, cryo-EM, endosome, lysosome, neurodegeneration, proteolysis",

author = "Andrew Chang and Xinyu Xiang and Jing Wang and Carolyn Lee and Tamta Arakhamia and Marija Simjanoska and Chi Wang and Yari Carlomagno and Guoan Zhang and Shikhar Dhingra and Manon Thierry and Jolien Perneel and Bavo Heeman and Forgrave, {Lauren M.} and Michael DeTure and DeMarco, {Mari L.} and Cook, {Casey N.} and Rosa Rademakers and Dickson, {Dennis W.} and Leonard Petrucelli and Stowell, {Michael H.B.} and Mackenzie, {Ian R.A.} and Fitzpatrick, {Anthony W.P.}",

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year = "2022",

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day = "14",

doi = "10.1016/j.cell.2022.02.026",

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T1 - Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases

AU - Chang, Andrew

AU - Xiang, Xinyu

AU - Wang, Jing

AU - Lee, Carolyn

AU - Arakhamia, Tamta

AU - Simjanoska, Marija

AU - Wang, Chi

AU - Carlomagno, Yari

AU - Zhang, Guoan

AU - Dhingra, Shikhar

AU - Thierry, Manon

AU - Perneel, Jolien

AU - Heeman, Bavo

AU - Forgrave, Lauren M.

AU - DeTure, Michael

AU - DeMarco, Mari L.

AU - Cook, Casey N.

AU - Rademakers, Rosa

AU - Dickson, Dennis W.

AU - Petrucelli, Leonard

AU - Stowell, Michael H.B.

AU - Mackenzie, Ian R.A.

AU - Fitzpatrick, Anthony W.P.

PY - 2022/4/14

Y1 - 2022/4/14

N2 - Misfolding and aggregation of disease-specific proteins, resulting in the formation of filamentous cellular inclusions, is a hallmark of neurodegenerative disease with characteristic filament structures, or conformers, defining each proteinopathy. Here we show that a previously unsolved amyloid fibril composed of a 135 amino acid C-terminal fragment of TMEM106B is a common finding in distinct human neurodegenerative diseases, including cases characterized by abnormal aggregation of TDP-43, tau, or α-synuclein protein. A combination of cryoelectron microscopy and mass spectrometry was used to solve the structures of TMEM106B fibrils at a resolution of 2.7 Å from postmortem human brain tissue afflicted with frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP, n = 8), progressive supranuclear palsy (PSP, n = 2), or dementia with Lewy bodies (DLB, n = 1). The commonality of abundant amyloid fibrils composed of TMEM106B, a lysosomal/endosomal protein, to a broad range of debilitating human disorders indicates a shared fibrillization pathway that may initiate or accelerate neurodegeneration.

AB - Misfolding and aggregation of disease-specific proteins, resulting in the formation of filamentous cellular inclusions, is a hallmark of neurodegenerative disease with characteristic filament structures, or conformers, defining each proteinopathy. Here we show that a previously unsolved amyloid fibril composed of a 135 amino acid C-terminal fragment of TMEM106B is a common finding in distinct human neurodegenerative diseases, including cases characterized by abnormal aggregation of TDP-43, tau, or α-synuclein protein. A combination of cryoelectron microscopy and mass spectrometry was used to solve the structures of TMEM106B fibrils at a resolution of 2.7 Å from postmortem human brain tissue afflicted with frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP, n = 8), progressive supranuclear palsy (PSP, n = 2), or dementia with Lewy bodies (DLB, n = 1). The commonality of abundant amyloid fibrils composed of TMEM106B, a lysosomal/endosomal protein, to a broad range of debilitating human disorders indicates a shared fibrillization pathway that may initiate or accelerate neurodegeneration.

KW - DLB

KW - FTLD-TDP

KW - PSP

KW - TMEM106B

KW - amyloid fibrils

KW - cryo-EM

KW - endosome

KW - lysosome

KW - neurodegeneration

KW - proteolysis

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AN - SCOPUS:85127928072

SN - 0092-8674

VL - 185

SP - 1346-1355.e15

JO - Cell

JF - Cell

IS - 8

ER -

Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases

Abstract

Keywords

ASJC Scopus subject areas

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