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TitleAmyloid fibrils in FTLD-TDP are composed of TMEM106B and not TDP-43.
Journal, issue, pagesNature, Vol. 605, Issue 7909, Page 304-309, Year 2022
Publish dateMar 28, 2022
AuthorsYi Xiao Jiang / Qin Cao / Michael R Sawaya / Romany Abskharon / Peng Ge / Michael DeTure / Dennis W Dickson / Janine Y Fu / Rachel R Ogorzalek Loo / Joseph A Loo / David S Eisenberg /
PubMed AbstractFrontotemporal lobar degeneration (FTLD) is the third most common neurodegenerative condition after Alzheimer's and Parkinson's diseases. FTLD typically presents in 45 to 64 year olds with ...Frontotemporal lobar degeneration (FTLD) is the third most common neurodegenerative condition after Alzheimer's and Parkinson's diseases. FTLD typically presents in 45 to 64 year olds with behavioural changes or progressive decline of language skills. The subtype FTLD-TDP is characterized by certain clinical symptoms and pathological neuronal inclusions with TAR DNA-binding protein (TDP-43) immunoreactivity. Here we extracted amyloid fibrils from brains of four patients representing four of the five FTLD-TDP subclasses, and determined their structures by cryo-electron microscopy. Unexpectedly, all amyloid fibrils examined were composed of a 135-residue carboxy-terminal fragment of transmembrane protein 106B (TMEM106B), a lysosomal membrane protein previously implicated as a genetic risk factor for FTLD-TDP. In addition to TMEM106B fibrils, we detected abundant non-fibrillar aggregated TDP-43 by immunogold labelling. Our observations confirm that FTLD-TDP is associated with amyloid fibrils, and that the fibrils are formed by TMEM106B rather than TDP-43.
External linksNature / PubMed:35344984 / PubMed Central
MethodsEM (helical sym.)
Resolution2.9 - 3.7 Å
Structure data

24953

7saq

EMDB-24953, PDB-7saq:
Cryo-EM structure of TMEM106B fibrils extracted from a FTLD-TDP patient, polymorph 1
Method: EM (helical sym.) / Resolution: 2.9 Å

24954

7sar

EMDB-24954, PDB-7sar:
Cryo-EM structure of TMEM106B fibrils extracted from a FTLD-TDP patient, polymorph 2
Method: EM (helical sym.) / Resolution: 3.2 Å

24955

7sas

EMDB-24955, PDB-7sas:
Cryo-EM structure of TMEM106B fibrils extracted from a FTLD-TDP patient, polymorph 3
Method: EM (helical sym.) / Resolution: 3.7 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • homo sapiens (human)
  • Human (human)
KeywordsPROTEIN FIBRIL / TMEM106B / FTLD-TDP / amyloid

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