. Patient-derived frontotemporal lobar degeneration brain extracts induce formation and spreading of TDP-43 pathology in vivo. Nat Commun. 2018 Oct 11;9(1):4220. PubMed.


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  1. In this paper, Porta et al. report that pathological TDP-43 derived from FTLD-TDP brains induced formation of de novo TDP-43 pathology, with subsequent spreading throughout the central nervous system in a regional- and time-dependent manner, in experimental animal models. This is big progress.

    It has been already confirmed that α-synuclein and tau protein pathologies are propagated in cellular and animal models. The propagation of TDP-43 pathology was observed in a cellular model (Nonaka et al., 2013), but so far the animal model was not successful.

    This paper indicates that cytoplasmic localization of TDP-43 is important for seeding and propagation of TDP-43 pathology. Unlike α-synuclein and tau, TDP-43 pathology propagation does not easily progress in non-transgenic mice because TDP-43 is localized in the nucleus. Therefore, overexpression and mislocalization of TDP-43 in the cytoplasm may be very important. In addition, Porta et al. used CamKIIa-208 tg-mice, which produced C-terminal fragment TDP-43, for their propagation study, and showed that in these mice propagation efficiency is lower as compared to CamKIIa-hTDP-43NLSm mice; this suggests that the N-terminal region of TDP-43 is important for fibril formation and propagation.

    TDP-43 proteinopathy has been classified into four types based on the predominant TDP-43-positive structures: type A mainly includes FTLD-TDP with GRN mutations, type B contains ALS and FTLD- MND, type C is representative of sporadic FTLD-TDP showing impairment of semantic memory, and type D refers to the pathology associated with IBM and VCP mutations (Mackenzie et al., 2011). Each type is also characterized biochemically by the patterns of insoluble TDP-43 CTFs and protease-resistant CTFs detected with anti-pTDP (Hasegawa et al., 2008Tsuji et al., 2012). Porta et al. here describe that no specific subtypes explained the differences found in vivo seeding activity. Hence it is necessary to further analyze the relationship between seeding activity or strain-like properties of pathological TDP-43 in patients and neuropathological phenotypes of the mice injected.


    . Prion-like properties of pathological TDP-43 aggregates from diseased brains. Cell Rep. 2013 Jul 11;4(1):124-34. PubMed.

    . Distinct pathological subtypes of FTLD-FUS. Acta Neuropathol. 2011 Feb;121(2):207-18. PubMed.

    . Phosphorylated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Ann Neurol. 2008 Jul;64(1):60-70. PubMed.

    . Molecular analysis and biochemical classification of TDP-43 proteinopathy. Brain. 2012 Nov;135(Pt 11):3380-91. Epub 2012 Oct 3 PubMed.

    View all comments by Masato Hasegawa

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  1. TDP-43 Joins Cell-To-Cell Propagation Gang