FTLD-TDP assemblies seed neoaggregates with subtype-specific features via a prion-like cascade.
FTLD-TDP
TDP-43
TDP-43 strains
frontotemporal dementia
prion-like
Journal
EMBO reports
ISSN: 1469-3178
Titre abrégé: EMBO Rep
Pays: England
ID NLM: 100963049
Informations de publication
Date de publication:
06 12 2021
06 12 2021
Historique:
revised:
29
10
2021
received:
25
08
2021
accepted:
02
11
2021
pubmed:
23
11
2021
medline:
15
3
2022
entrez:
22
11
2021
Statut:
ppublish
Résumé
Morphologically distinct TDP-43 aggregates occur in clinically different FTLD-TDP subtypes, yet the mechanism of their emergence and contribution to clinical heterogeneity are poorly understood. Several lines of evidence suggest that pathological TDP-43 follows a prion-like cascade, but the molecular determinants of this process remain unknown. We use advanced microscopy techniques to compare the seeding properties of pathological FTLD-TDP-A and FTLD-TDP-C aggregates. Upon inoculation of patient-derived aggregates in cells, FTLD-TDP-A seeds amplify in a template-dependent fashion, triggering neoaggregation more efficiently than those extracted from FTLD-TDP-C patients, correlating with the respective disease progression rates. Neoaggregates are sequentially phosphorylated with N-to-C directionality and with subtype-specific timelines. The resulting FTLD-TDP-A neoaggregates are large and contain densely packed fibrils, reminiscent of the pure compacted fibrils present within cytoplasmic inclusions in postmortem brains. In contrast, FTLD-TDP-C dystrophic neurites show less dense fibrils mixed with cellular components, and their respective neoaggregates are small, amorphous protein accumulations. These cellular seeding models replicate aspects of the patient pathological diversity and will be a useful tool in the quest for subtype-specific therapeutics.
Identifiants
pubmed: 34806807
doi: 10.15252/embr.202153877
pmc: PMC8647015
doi:
Substances chimiques
Prions
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e53877Informations de copyright
© 2021 The Authors. Published under the terms of the CC BY NC ND 4.0 license.
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