TDP-43 extracted from frontotemporal lobar degeneration subject brains displays distinct aggregate assemblies and neurotoxic effects reflecting disease progression rates.

Details

Serval ID
serval:BIB_F53DD6E457F9
Type
Article: article from journal or magazin.
Collection
Publications
Title
TDP-43 extracted from frontotemporal lobar degeneration subject brains displays distinct aggregate assemblies and neurotoxic effects reflecting disease progression rates.
Journal
Nature neuroscience
Author(s)
Laferrière F., Maniecka Z., Pérez-Berlanga M., Hruska-Plochan M., Gilhespy L., Hock E.M., Wagner U., Afroz T., Boersema P.J., Barmettler G., Foti S.C., Asi Y.T., Isaacs A.M., Al-Amoudi A., Lewis A., Stahlberg H., Ravits J., De Giorgi F., Ichas F., Bezard E., Picotti P., Lashley T., Polymenidou M.
ISSN
1546-1726 (Electronic)
ISSN-L
1097-6256
Publication state
Published
Issued date
01/2019
Peer-reviewed
Oui
Volume
22
Number
1
Pages
65-77
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Accumulation of abnormally phosphorylated TDP-43 (pTDP-43) is the main pathology in affected neurons of people with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Morphological diversity and neuroanatomical distribution of pTDP-43 accumulations allowed classification of FTLD cases into at least four subtypes, which are correlated with clinical presentations and genetic causes. To understand the molecular basis of this heterogeneity, we developed SarkoSpin, a new method for biochemical isolation of pathological TDP-43. By combining SarkoSpin with mass spectrometry, we revealed proteins beyond TDP-43 that become abnormally insoluble in a disease subtype-specific manner. We show that pTDP-43 extracted from brain forms stable assemblies of distinct densities and morphologies that are associated with disease subtypes. Importantly, biochemically extracted pTDP-43 assemblies showed differential neurotoxicity and seeding that were correlated with disease duration of FTLD subjects. Our data are consistent with the notion that disease heterogeneity could originate from alternate pathological TDP-43 conformations, which are reminiscent of prion strains.
Keywords
Animals, Brain/metabolism, Brain/pathology, DNA-Binding Proteins/metabolism, Disease Progression, Frontotemporal Lobar Degeneration/metabolism, Frontotemporal Lobar Degeneration/pathology, HEK293 Cells, Humans, Inclusion Bodies/metabolism, Inclusion Bodies/pathology, Mass Spectrometry, Mice, Neurons/metabolism, Neurons/pathology, Phosphorylation, Protein Aggregates/physiology
Pubmed
Web of science
Create date
09/06/2023 16:02
Last modification date
08/07/2023 6:50
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