. Structure of pathological TDP-43 filaments from ALS with FTLD. Nature. 2022 Jan;601(7891):139-143. Epub 2021 Dec 8 PubMed.


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  1. I am very pleased to see cyroEM data on TDP-43 filaments finally emerging, and I would like to congratulate the authors. In the study, the authors focused on the analysis of cortical TDP-43 aggregates isolated from human postmortem tissue from two ALS/FTLD type B TDP cases. They describe, for the first time, the structure of the pronase-resistant core of TDP-43 filaments.

    The reported evident structural differences from filaments formed by other proteins involved in neurodegenerative diseases, such as tau or α-synuclein, provide a good explanation for the well-described distinct behavior of TDP-43 aggregates with respect to binding to amyloid dyes, such as Thioflavin S. Also of particular note is the lack of agreement with reported TDP-43 filament structures from in vitro cryoEM studies, which supports the essential importance of postmortem tissue analysis for these kinds of studies.

    In the future, it will be crucial to learn if and how the structure of TDP-43 filaments differs among the various well-recognized subtypes of FTLD-TDP. Moreover, given the well-recognized difference in the composition of TDP-43 inclusions in the spinal cord/brainstem compared to those in cortical CNS regions in terms of abundance of full-length versus C-terminal fragments, it will be also very interesting and important to see whether the structure of the filaments will be also consistent across these different CNS regions.

    View all comments by Manuela Neumann
  2. This exciting work presents the first atomic structures of pathological amyloid fibrils of TDP-43 extracted from the brains of two patients who suffered from ALS with FTLD. The TDP-43 fibrils exhibit a novel compact double-spiral-shaped fold. Given the important role of TDP-43 aggregation in ALS, FTLD and some other neurodegenerative diseases, this work provides an important starting point to understand the structure-pathology relationship of TDP-43 aggregation in diseases.

    Interestingly, unlike α-synuclein and Aβ fibrils, both of which show structural similarity between in vitro-prepared and brain-derived fibrils to some extent (Schweighauser et al., 2020; Li et al., 2018; Li et al., 2018; Yang et al., 2021; Schütz et al., 2015), TDP-43 fibril is completely distinct from those prepared in vitro in terms of helical chirality, secondary structure, and the size of fibril core. This observation suggests a high degree of conformational plasticity of TDP-43 in forming fibrils which may be due to the low-complexity nature of its primary sequence. Indeed, different TDP-43 strains were previously identified in the brains of different FTLD-TDP subtypes with distinct pathological properties (Porta et al., 2021). It will be interesting to see whether TDP-43 adopts different atomic structures in fibrils of other subtypes.

    If so, a question will be how the double-spiral-shaped fold of TDP-43 fibril is determined in the brain of a patient with ALS with FTLD? Previous studies showed that PTM and ligands may play an important role in fibril polymorph selection (Li and Liu, 2021; Arakhamia et al., 2020). Indeed, several unidentified densities were observed adjacent to the TDP-43 fibril surface formed by Q286, R293 and A315. Identification of these unknown ligands may provide a clue for fibril polymorph selection. 

    Given the resolution revolution of cryo-EM, more and more amyloid fibril structures assembled in vitro or extracted from brains were determined in the past few years. However, a key question remains to be answered: How do amyloid fibril structures explain their pathologies? The connection between fibril structure and pathology needs to be established.


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    View all comments by Dan Li

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  1. Double Spiral Sets TDP-43 Apart from Other Amyloids