Journal ArticleDOI
Distinct brain-derived TDP-43 strains from FTLD-TDP subtypes induce diverse morphological TDP-43 aggregates and spreading patterns in vitro and in vivo.
Sílvia Porta,Yan Xu,Tagan Lehr,Bin Zhang,Emily S. Meymand,Modupe F. Olufemi,Anna Stieber,Edward B. Lee,John Q. Trojanowski,Virginia M.-Y. Lee +9 more
TLDR
In this article, the authors evaluated the existence of distinct TDP-43 strains in the brains of different FTLD-TDP subtypes and characterised their specific seeding properties in vitro and in vivo.Abstract:
Aim The heterogeneity in the distribution and morphological features of TAR DNA-binding protein-43 (TDP-43) pathology in the brains of frontotemporal lobar degeneration (FTLD-TDP) patients and their different clinical manifestations suggest that distinct pathological TDP-43 strains could play a role in this heterogeneity between different FTLD-TDP subtypes (A-E). Our aim was to evaluate the existence of distinct TDP-43 strains in the brains of different FTLD-TDP subtypes and characterise their specific seeding properties in vitro and in vivo. Methods and results We used an inducible stable cell line expressing a mutant cytoplasmic TDP-43 (iGFP-NLSm) to evaluate the seeding properties of distinct pathological TDP-43 strains. Brain-derived TDP-43 protein extracts from FTLD-TDP types A (n = 6) and B (n = 3) cases induced the formation of round/spherical phosphorylated TDP-43 aggregates that morphologically differed from the linear and wavy wisps and bigger heterogeneous filamentous (skein-like) aggregates induced by type E (n = 3) cases. These morphological differences correlated with distinct biochemical banding patterns of sarkosyl-insoluble TDP-43 protein recovered from the transduced cells. Moreover, brain-derived TDP-43 extracts from type E cases showed higher susceptibility to PK digestion of full-length TDP-43 and the most abundant C-terminal fragments that characterise type E extracts. Finally, we showed that intracerebral injections of different TDP-43 strains induced a distinctive morphological and subcellular distribution of TDP-43 pathology and different spreading patterns in the brains of CamKIIa-hTDP-43NLSm Tg mice. Conclusions We show the existence of distinct TDP-43 strains in the brain of different FTLD-TDP subtypes with distinctive seeding and spreading properties in the brains of experimental animal models.read more
Citations
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Journal ArticleDOI
Structural and Functional Insights into α-Synuclein Fibril Polymorphism
TL;DR: In this article, the authors discuss clinical and pathological variability in synucleinopathies and several aspects of α-Syn fibril polymorphism, including the existence of high-resolution molecular structures and brain-derived strains.
Journal ArticleDOI
TDP-43 pathology: From noxious assembly to therapeutic removal
TL;DR: In this article , the authors explore how the pathogenic changes to TDP-43, including mislocalisation, misfolding, aberrant liquid-liquid phase separation, stress granule assembly, oligomerization, and post-translational modification, drive diseaseassociated aggregation in TDP43 proteinopathies.
Journal ArticleDOI
The Cellular Prion Protein Increases the Uptake and Toxicity of TDP-43 Fibrils
Carlo Scialò,Luigi Celauro,Marco Zattoni,Thanh Hoa Tran,Edoardo Bistaffa,Fabio Moda,Robert Kammerer,Emanuele Buratti,Giuseppe Legname +8 more
TL;DR: In this paper, the authors exploited two different cellular systems (human SH-SY5Y and mouse N2a neuroblastoma cells) engineered to express low or high PrPC levels to investigate the link between PrPC expression on the cell surface and the internalization of TDP-43 fibrils.
Journal ArticleDOI
FTLD-TDP assemblies seed neoaggregates with subtype-specific features via a prion-like cascade.
Pierre De Rossi,Amanda J Lewis,Johanna Furrer,Laura De Vos,Tomas Demeter,Aurélie Zbinden,Weijia Zhong,Vera I. Wiersma,Carlo Scialo,Julien Weber,Zhongning Guo,Stefano Scaramuzza,Marta Di Fabrizio,Carolin Böing,Daniel Castaño-Díez,Ashraf Al-Amoudi,Manuela Pérez-Berlanga,Tammaryn Lashley,Henning Stahlberg,Magdalini Polymenidou +19 more
TL;DR: In this paper, advanced microscopy techniques were used to compare the seeding properties of pathological TDP-TDP-A and FTLD-TPD-C aggregates. And the results showed that the resulting aggregates are large and contain densely packed fibrils, reminiscent of the pure compacted Fibrils present within cytoplasmic inclusions in postmortem brains.
Journal ArticleDOI
pTDP‐43 aggregates accumulate in non‐central nervous system tissues prior to symptom onset in amyotrophic lateral sclerosis: a case series linking archival surgical biopsies with clinical phenotypic data
Samuel B Pattle,Judi O’Shaughnessy,Owen Kantelberg,Olivia M. Rifai,Judith A. Pate,Kristine Nellany,Nadine Hays,Mark J. Arends,Mathew H. Horrocks,Fergal M Waldron,Jenna M. Gregory +10 more
TL;DR: In all cases with non-CNS pTDP-43 pathology, aggregates were present prior to ALS diagnosis and in some instances preceded neurological symptom onset by more than 10 years, implying that patients with microscopically unexplained non-central nervous system symptoms could have occult protein aggregation that could be detected many years prior to neurological involvement.
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