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TitleHomotypic fibrillization of TMEM106B across diverse neurodegenerative diseases.
Journal, issue, pagesCell, Vol. 185, Issue 8, Page 1346-1355.e15, Year 2022
Publish dateApr 14, 2022
AuthorsAndrew 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 /
PubMed AbstractMisfolding and aggregation of disease-specific proteins, resulting in the formation of filamentous cellular inclusions, is a hallmark of neurodegenerative disease with characteristic filament ...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.
External linksCell / PubMed:35247328 / PubMed Central
MethodsEM (helical sym.)
Resolution2.7 - 23.0 Å
Structure data

26268

7u0z

EMDB-26268, PDB-7u0z:
High-resolution map of tau filament from progressive supranuclear palsy (PSP) case 1
Method: EM (helical sym.) / Resolution: 4.2 Å

26273

7u10

EMDB-26273, PDB-7u10:
TMEM106B(120-254) protofilament from progressive supranuclear palsy (PSP) case 2
Method: EM (helical sym.) / Resolution: 3.0 Å

26274

7u11

EMDB-26274, PDB-7u11:
TMEM106B(120-254) protofilament from frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) type A (case 1)
Method: EM (helical sym.) / Resolution: 3.2 Å

26275

7u12

EMDB-26275, PDB-7u12:
TMEM106B(120-254) singlet amyloid fibril from frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) type A (case 2)
Method: EM (helical sym.) / Resolution: 3.5 Å

26276

7u13

EMDB-26276, PDB-7u13:
TMEM106B(120-254) singlet amyloid fibril from frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) type A (case 4)
Method: EM (helical sym.) / Resolution: 2.9 Å

26277

7u14

EMDB-26277, PDB-7u14:
TMEM106B(120-254) singlet amyloid fibril from frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) type C (case 8)
Method: EM (helical sym.) / Resolution: 4.5 Å

26278

7u15

7u17

EMDB-26278, PDB-7u15:
TMEM106B(120-254) singlet amyloid fibril from frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) type B case 2 (case 7).
PDB-7u17: TMEM106B(120-254) T185S singlet amyloid fibril from frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) type B case 2 (case 7).
Method: EM (helical sym.) / Resolution: 3.0 Å

26279

7u16

7u18

EMDB-26279, PDB-7u16:
TMEM106B(120-254) protofilament from frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) type A (all cases combined).
PDB-7u18: TMEM106B(120-254) T185S protofilament from frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) type A (all cases combined).
Method: EM (helical sym.) / Resolution: 2.7 Å

EMDB-26281: TMEM106B(120-254) singlet amyloid fibril from dementia with Lewy bodies (DLB).
Method: EM (helical sym.) / Resolution: 7.6 Å

EMDB-26282: TMEM106B(120-254) doublet amyloid fibril from dementia with Lewy bodies (DLB).
Method: EM (helical sym.) / Resolution: 8.8 Å

EMDB-26283: Low-resolution map of tau filament from progressive supranuclear palsy (PSP) case 3.
Method: EM (helical sym.) / Resolution: 23.0 Å

EMDB-26284: TMEM106B(120-254) singlet amyloid fibril from progressive supranuclear palsy (PSP) case 1.
Method: EM (helical sym.) / Resolution: 4.4 Å

EMDB-26285: TMEM106B(120-254) singlet amyloid fibril from progressive supranuclear palsy (PSP) case 2.
Method: EM (helical sym.) / Resolution: 3.6 Å

EMDB-26286: TMEM106B(120-254) doublet amyloid fibril from progressive supranuclear palsy (PSP) case 2.
Method: EM (helical sym.) / Resolution: 3.6 Å

EMDB-26287:
TMEM106B(120-254) doublet amyloid fibril from frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) type C (case 8).
Method: EM (helical sym.) / Resolution: 4.4 Å

EMDB-26288:
TMEM106B(120-254) singlet amyloid fibril from frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) type B (case 6).
Method: EM (helical sym.) / Resolution: 7.2 Å

EMDB-26289:
TMEM106B(120-254) doublet amyloid fibril from frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) type A (case 5).
Method: EM (helical sym.) / Resolution: 6.9 Å

EMDB-26290:
TMEM106B(120-254) doublet amyloid fibril from frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) type A (case 4).
Method: EM (helical sym.) / Resolution: 2.8 Å

EMDB-26291:
TMEM106B(120-254) doublet amyloid fibril from frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) type A (case 3).
Method: EM (helical sym.) / Resolution: 7.0 Å

EMDB-26292:
TMEM106B(120-254) singlet amyloid fibril from frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) type A (case 3).
Method: EM (helical sym.) / Resolution: 4.5 Å

EMDB-26293:
TMEM106B(120-254) doublet amyloid fibril from frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) type A (case 2).
Method: EM (helical sym.) / Resolution: 4.3 Å

EMDB-26294:
TMEM106B(120-254) doublet amyloid fibril from frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) type A (case 1).
Method: EM (helical sym.) / Resolution: 3.1 Å

EMDB-26295:
TMEM106B(120-254) singlet amyloid fibril from frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) type A (case 1).
Method: EM (helical sym.) / Resolution: 3.4 Å

EMDB-26296:
TMEM106B(120-254) singlet amyloid fibril from frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) type A (all cases combined).
Method: EM (helical sym.) / Resolution: 3.0 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

Source
  • homo sapiens (human)
KeywordsPROTEIN FIBRIL / Tau protein / Amyloid fibril / TMEM106B / TRANSPORT PROTEIN / UNKNOWN FUNCTION

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