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

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 classificati...

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Vydáno v:	Nature neuroscience Ročník 22; číslo 1; s. 65 - 77
Hlavní autoři:	Laferrière, Florent, Maniecka, Zuzanna, Pérez-Berlanga, Manuela, Hruska-Plochan, Marian, Gilhespy, Larissa, Hock, Eva-Maria, Wagner, Ulrich, Afroz, Tariq, Boersema, Paul J, Barmettler, Gery, Foti, Sandrine C, Asi, Yasmine T, Isaacs, Adrian M, Al-Amoudi, Ashraf, Lewis, Amanda, Stahlberg, Henning, Ravits, John, De Giorgi, Francesca, Ichas, François, Bezard, Erwan, Picotti, Paola, Lashley, Tammaryn, Polymenidou, Magdalini
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Nature Publishing Group 01.01.2019
Témata:	Aggregates Amyotrophic lateral sclerosis Anatomy Animals Assemblies Brain Brain - metabolism Brain - pathology Brain architecture Degeneration Dementia Disease Progression DNA-Binding Proteins - metabolism Frontotemporal dementia Frontotemporal Lobar Degeneration - metabolism Frontotemporal Lobar Degeneration - pathology HEK293 Cells Heterogeneity Humans Inclusion Bodies - metabolism Inclusion Bodies - pathology Mass Spectrometry Mass spectroscopy Medical research Mice Morphology Motor neurone disease Mutation Neurodegeneration Neurology Neurons - metabolism Neurons - pathology Neuropathology Neurosciences Neurotoxicity Pathology Phosphorylation Physiology Protein Aggregates - physiology Protein seeding Proteins Scientific imaging Semantics
ISSN:	1097-6256, 1546-1726, 1546-1726
On-line přístup:	Získat plný text
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Popis
Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1097-6256 1546-1726 1546-1726
DOI:	10.1038/s41593-018-0294-y