. Full-length TDP-43 forms toxic amyloid oligomers that are present in frontotemporal lobar dementia-TDP patients. Nat Commun. 2014 Sep 12;5:4824. PubMed.


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  1. In this comprehensive and multifaceted study, Ruby Chen and her coworkers demonstrated that TDP-43, a protein associated with frontotemporal lobar dementia and amyotrophic lateral sclerosis, assembles into a heterogeneous population of quasispherical and annual oligomers, reminiscent of similarly shaped multimers known to play a critical role in other amyloidogenic disorders, such as Alzheimer's and Parkinson's diseases. The study shows that TDP-43 oligomers are toxic in vitro and in vivo, suggesting that a pathogenic mechanism akin to the mechanism postulated in other amyloid pathologies may be at play. TDP-43, however, performs an important function in RNA metabolism and its absence seems to be lethal at the embryonic stage. As TDP-43 oligomers relative to monomers exhibited reduced TDP-43 binding to DNA and RNA, this loss of function upon oligomerization may additionally contribute to the pathology.

    I was not convinced about the interpretation of the PICUP/SDS-PAGE data, which led the authors to conclude that TDP-43 oligomers seed Aβ40 oligomerization. Their evidence is based on a TDP-43 concentration-dependent presence of a ~55 kDa species in the PAGE gel, as well as other species with a molecular mass above ~100 kDa. It is known that Aβ40 alone readily forms dimers through tetramers, while pentamer and hexamer bands are much less significant (Bitan et al., 2003). The interpretation of PICUP/SDS-PAGE data for a solution containing two proteins of very different lengths (40 and 414 residues comprising Aβ40 and TDP-43, respectively) is tricky, as discussed in a study that examined the mechanism of the C-terminal Aβ fragments as inhibitors of Aβ42 oligomer toxicity (Fradinger et al., 2008). During PICUP, tyrosine (and possibly other aromatic amino acids) are involved in covalent cross-linking. The species with a molecular mass of ~55 kDa could correspond to a covalently cross-linked complex of TDP-43 (with a molecular mass of 47 kDa) and Aβ40 dimer, for example. Given that TDP-43 is more than 10 times longer than Aβ40, this is a plausible scenario that would also explain why the presence of TDP-43 abolishes Aβ40 fibril formation, as Aβ40 peptides that form a stable complex with TDP-43 could not structurally convert into fibrils. This aspect of the study would benefit from further examination.

    Detection and characterization of TDP-43 oligomers fits well into a general paradigm of a common structural motif across a broad class of amyloidogenic proteins which self-associate into heterogeneous quasispherical and/or annual oligomers, eventually forming fibers that can be detected by dyes such as Thioflavin T and Congo Red. From the point of view of statistical physics and thermodynamics, such a self-assembly pathway is not surprising, as we demonstrated recently by invoking a minimal model of self-assembly that captures universal assembly pathways from monomers through quasispherical oligomers into elongated multidomain fibril-like morphologies (Barz and Urbanc, 2014).

    Considering that the population of TDP-43 oligomers Ruby Chen and her collaborators observed was heterogeneous and characterized by some degree of hydrophobic exposure, one would expect that these oligomers would further aggregate into larger species, although the corresponding structural conversion in TDP-43 might be significantly slower than in the case of the much shorter Aβ. Insights into this structural conversion process, if it indeed exists and can be unambiguously detected, might elucidate the missing link between the reported oligomers and the inclusion bodies, which are the pathologic hallmarks of frontotemporal lobar dementia.


    . Amyloid beta -protein (Abeta) assembly: Abeta 40 and Abeta 42 oligomerize through distinct pathways. Proc Natl Acad Sci U S A. 2003 Jan 7;100(1):330-5. PubMed.

    . C-terminal peptides coassemble into Abeta42 oligomers and protect neurons against Abeta42-induced neurotoxicity. Proc Natl Acad Sci U S A. 2008 Sep 16;105(37):14175-80. PubMed.

    . Minimal model of self-assembly: emergence of diversity and complexity. J Phys Chem B. 2014 Apr 10;118(14):3761-70. Epub 2014 Mar 6 PubMed.

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  1. Does TDP-43 Oligomerize and Coax Aβ to Do the Same?