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

Laferrière, Florent and Maniecka, Zuzanna and Pérez-Berlanga, Manuela and Hruska-Plochan, Marian and Gilhespy, Larissa and Hock, Eva-Maria and Wagner, Ulrich and Afroz, Tariq and Boersema, Paul J. and Barmettler, Gery and Foti, Sandrine C. and Asi, Yasmine T. and Isaacs, Adrian M. and Al-Amoudi, Ashraf and Lewis, Amanda and Stahlberg, Henning and Ravits, John and De Giorgi, Francesca and Ichas, François and Bezard, Erwan and Picotti, Paola and Lashley, Tammaryn and Polymenidou, Magdalini. (2019) TDP-43 extracted from frontotemporal lobar degeneration subject brains displays distinct aggregate assemblies and neurotoxic effects reflecting disease progression rates. Nature neuroscience, 22 (1). pp. 65-77.

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Official URL: https://edoc.unibas.ch/67452/

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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.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Structural Biology (Stahlberg)
UniBasel Contributors:Stahlberg, Henning
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Nature America
ISSN:1097-6256
e-ISSN:1546-1726
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:17 Sep 2020 09:46
Deposited On:17 Sep 2020 09:46

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