Arseni D, Nonaka T, Jacobsen MH, Murzin AG, Cracco L, Peak-Chew SY, Garringer HJ, Kawakami I, Suzuki H, Onaya M, Saito Y, Muryama S, Geula C, Vidal R, Newell KL, Mesulam M, Ghetti B, Hasegawa M, Ryskeldi-Falcon B. Heteromeric amyloid filaments of ANXA11 and TDP-43 in FTLD-TDP Type C. 2024 Jun 26 10.1101/2024.06.25.600403 (version 1) bioRxiv.

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  1. In the beginning, amyloid was identified by tell-tale morphologic and staining characteristics, and little was known about its constituent proteins. As analytic methods progressed, amyloids became increasingly defined by their principal polymeric proteins, of which more than 40 are now known (Buxbaum et al., 2022). Although amyloid filaments are superficially similar, in recent years, it has become evident that the three-dimensional structure of the filaments formed by a given protein can vary, and that this variation can influence the resulting disease phenotype. Cryo-electron microscopy (cryo-EM) has played a key role in advancing this concept.

    While the number of such studies is still small, prior cryo-EM investigations had consistently found that individual amyloid filaments from diseased tissues consisted of a single type of misfolded protein. Various analyses have detected other (usually minor) molecular components of amyloid deposits, but their precise localization and pathogenic importance have mostly been uncertain, and none of them have been shown to be integral constituents of amyloid filaments per se. By demonstrating the coherent integration of two different proteins, annexin-A11 and TDP-43,  into individual amyloid filaments from persons with FTLD-TDP Type C, Arseni and colleagues convincingly revise the "one filament, one protein" concept, and raise intriguing questions about amyloidogenesis in general. 

    The researchers present evidence that annexin-A11 and TDP-43 co-assemble, rather than polymerizing separately into protofilaments that become entwined; does this suggest the presence of heteromeric oligomers, and if so, what are their characteristics? And do heteromeric multimers act as proteopathic seeds, and how might these interact with two separate proteins to induce the formation of heteromeric filaments?

    It will be important to determine whether heteromeric filaments occur in other amyloidoses (where they might influence the disease phenotype), or whether the polymers of annexin-A11 and TDP-43 in Type C FTLD-TDP are unique. In this regard, while most auxiliary molecular entities within amyloids probably are not intrinsic to the filaments, revisiting their structural relationship to the filaments with methods such as cryo-EM might shed new light on the ontogeny of the lesions. 

    The analysis of amyloids by cryo-EM is still in its early stages, yet already it has generated important insights into the surprisingly varied molecular architecture of amyloid filaments. It is gratifying to consider how much we have learned about amyloid and amyloidoses since the advent of the Congo red stain a century ago, but as the elegant work of Arseni and colleagues shows, there is still plenty to learn. 

    References:

    Buxbaum JN, Dispenzieri A, Eisenberg DS, Fändrich M, Merlini G, Saraiva MJ, Sekijima Y, Westermark P. Amyloid nomenclature 2022: update, novel proteins, and recommendations by the International Society of Amyloidosis (ISA) Nomenclature Committee. Amyloid. 2022 Dec;29(4):213-219. Epub 2022 Nov 24 PubMed.

    View all comments by Lary Walker

  2. I think this is a very interesting and exciting discovery for several reasons.

    1. The finding of a novel type of filament as a consistent feature of FTLD-TDP type C samples confirms that these cases represent a distinct entity, and validates the current pathological classification.
    2. The identification of the first heteromeric filaments associated with neurodegenerative disease suggests a new way in which pathological proteins might interact that may be relevant to a number of other conditions.
    3. The association of ANXA11 with a subtype of FTLD and the previous reports of ANXA11 mutations in ALS further support the molecular overlap between FTD and ALS.
    4. The possible role of ANXA11 in contributing to neurodegenerative disease is intriguing, given its association with RNA granules and lysosomes; however, the specificity of this association will require additional research given the recent reports that ANXA11 aggregates are an inconsistent feature in a variety of different neurodegenerative conditions (Robinson et al., 2024). 

    References:

    Robinson JL, Suh E, Xu Y, Hurtig HI, Elman L, McMillan CT, Irwin DJ, Porta S, Van Deerlin VM, Lee EB. Annexin A11 aggregation in FTLD-TDP type C and related neurodegenerative disease proteinopathies. Acta Neuropathol. 2024 Jun 19;147(1):104. PubMed.

    View all comments by Ian Mackenzie

  3. These parallel discoveries by the Lee and Ryskeldi-Falcon teams are seminal. Together, they conclusively show that two distinct proteins, ANXA11 and TDP-43, co-assemble into organized heteromeric amyloid filaments in FTLD type C and in a subset of other TDP-43 proteinopathies. While previous studies hinted that aggregation-prone proteins could co-localize together in neurodegenerative diseases, most of us assumed that such aggregates were juxtaposed but structurally distinct. That ANXA11 and TDP-43 form interwoven filaments, proven by cryo-EM by the Ryskeldi-Falcon group and quantified pathologically by the Lee group, was entirely unexpected.

    These findings further hint at possible upstream origins of the co-filaments, rooted in the normal function of these proteins. Our team previously showed that ANXA11 tethers ribonucleoprotein (RNP) granules to lysosomes for long-distance transport in axons (Liao et al., 2019). At least a fraction of lysosome-associated RNP granules co-traffic with TDP-43, suggesting that ANXA11 and TDP-43 may normally co-assemble in phase condensates during RNA transport. One wonders if the residues bridging ANXA11 and TDP-43 within filamentous assemblies could functionally link these two proteins together within physiological RNPs, but also predispose them to pathological interactions during disease.

    There may be a broader role for ANXA11 in neurodegenerative disease than was initially believed. First linked to familial forms of ALS by Chris Shaw’s group, we now know that ANXA11 mutations can cause a range of neurodegenerative diseases. Our team recently found that corticobasal syndrome can be caused by ANXA11 mutations (Snyder et al., 2024), adding to a growing list of clinical syndromes within the ALS/FTD/MSP spectrum associated with mutations in this gene. Interestingly, Eddie Lee saw that approximately 6 percent of non-familial AD/LATE cases had co-pathology of ANXA11-TDP-43 co-aggregates. Given the relatively high prevalence of AD/LATE, this means that ANXA11 pathology is quite common, especially when compared to FTLD type C.

    References:

    Liao YC, Fernandopulle MS, Wang G, Choi H, Hao L, Drerup CM, Patel R, Qamar S, Nixon-Abell J, Shen Y, Meadows W, Vendruscolo M, Knowles TP, Nelson M, Czekalska MA, Musteikyte G, Gachechiladze MA, Stephens CA, Pasolli HA, Forrest LR, St George-Hyslop P, Lippincott-Schwartz J, Ward ME. RNA Granules Hitchhike on Lysosomes for Long-Distance Transport, Using Annexin A11 as a Molecular Tether. Cell. 2019 Sep 19;179(1):147-164.e20. PubMed.

    Snyder A, Ryan VH, Hawrot J, Lawton S, Ramos DM, Qi YA, Johnson KR, Reed X, Johnson NL, Kollasch AW, Duffy MF, VandeVrede L, Cochran JN, Miller BL, Toro C, Bielekova B, Marks DS, Yokoyama JS, Kwan JY, Cookson MR, Ward ME. An ANXA11 P93S variant dysregulates TDP-43 and causes corticobasal syndrome. Alzheimers Dement. 2024 Aug;20(8):5220-5235. Epub 2024 Jun 26 PubMed.

    View all comments by Michael Ward

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