Distinct brain‐derived TDP‐43 strains from FTLD‐TDP subtypes induce diverse morphological TDP‐43 aggregates and spreading patterns in vitro and in vivo

作者：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 · 发表于：Neuropathology and Applied Neurobiology · 年份：2021 · DOI：10.1111/nan.12732 · 被引用次数：62 · 研究领域：Amyotrophic Lateral Sclerosis Research、Parkinson's Disease Mechanisms and Treatments、Neurological disorders and treatments

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 stra...