Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases.
DLB
FTLD-TDP
PSP
TMEM106B
amyloid fibrils
cryo-EM
endosome
lysosome
neurodegeneration
proteolysis
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
14 04 2022
14 04 2022
Historique:
received:
25
01
2022
revised:
14
02
2022
accepted:
23
02
2022
pubmed:
6
3
2022
medline:
20
4
2022
entrez:
5
3
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35247328
pii: S0092-8674(22)00259-8
doi: 10.1016/j.cell.2022.02.026
pmc: PMC9018563
mid: NIHMS1784277
pii:
doi:
Substances chimiques
Amyloid
0
DNA-Binding Proteins
0
Membrane Proteins
0
Nerve Tissue Proteins
0
TMEM106B protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1346-1355.e15Subventions
Organisme : NIA NIH HHS
ID : R01 AG063780
Pays : United States
Organisme : NINDS NIH HHS
ID : U01 NS110438
Pays : United States
Organisme : CIHR
ID : 74580
Pays : Canada
Organisme : NINDS NIH HHS
ID : U54 NS110435
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG061829
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Published by Elsevier Inc.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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