Darwich NF, Phan JM, Kim B, Suh E, Papatriantafyllou JD, Changolkar L, Nguyen AT, O'Rourke CM, He Z, Porta S, Gibbons GS, Luk KC, Papageorgiou SG, Grossman M, Massimo L, Irwin DJ, McMillan CT, Nasrallah IM, Toro C, Aguirre GK, Van Deerlin VM, Lee EB. Autosomal dominant VCP hypomorph mutation impairs disaggregation of PHF-tau. Science. 2020 Nov 20;370(6519) Epub 2020 Oct 1 PubMed.

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  1. This study from Dr. Edward Lee’s group provides an exciting glimpse into the potential role of valosin-containing protein (VCP) in ameliorating tau aggregation. The work highlights a novel autosomal-dominant mutation (D395G) in the D1ATPase domain of VCP which results in early onset neurodegeneration in families. The associated neuropathology shows an interesting inverse relationship between the location of vacuoles and Alzheimer’s-like tau tangles in the brain. The authors have termed this frontotemporal degeneration “vacuolar tauopathy.”

    Through several in vitro experiments, the authors present evidence that the identified mutation inhibits the ATPase activity of VCP, decreasing its disaggregase activity on tau fibrils in vitro. They have further determined that a polyubiquitin signature on the substrate is essential for VCP’s disaggregation effect. Finally, the observation of increased tau pathology and spread in the knock-in mice expressing the mutant form of VCP recapitulates an essential function that it might play in curbing tau pathology, adding an important physiological test to their study.

    This finding is a major contribution to the field. It promises to be an important lead into further dissecting the mechanism(s) of tau aggregation or disaggregation. It lays a solid foundation of what could be an important role of VCP in tauopathies, and it raises several questions regarding our understanding of the tau assembly formation/breakdown process. To begin, it will be interesting to determine the stage(s) of tau aggregation (initiation/maintenance/clearance) and species of tau (monomer/oligomers/ aggregates) affected by VCP.

    Does tau ubiquitination precede VCP interactions, and, if so, what are the precise site(s) of ubiquitination, are they unique for distinct tauopathies, and how might ubiquitinated tau be routed for downstream processing? It is also intriguing, in light of other disaggregases such as HSP104 in yeast, to consider whether VCP might actually promote seeding in certain contexts. Given VCP’s links to the proteasome system, autophagy, and even stress granules, to name a few, it will be important to parse the pathways (or combinations of them) specific to clearance of tau fibrils. It will also be very interesting to determine the characteristics of the fragments generated by VCP’s disaggregase activity. For example, does the breakdown by VCP create benign tau species incapable of aggregating or does it release pathogenic monomers/oligomers that can continue to function as seeds?

    Overall, Lee and colleagues should be congratulated on their rigorous work, which has linked disparate diseases through a common factor, and has set the stage for many further exciting studies.

    View all comments by Sushobhna Batra

  2. This is an impressive new paper. The identification of a new mutation in a chaperone protein that causes a novel tauopathy is very exciting. Links between VCP and tau have been made over the last 10 years by a number of groups. These data significantly strengthen this connection and provide strong evidence of a newly identified functional role for VCP in disaggregating AD-tau PHFs in an ATP- and polyubiquitin-dependent manner.

    Future studies are needed to determine how this VCP mutation affects autophagy, proteasome degradation, and ER stress and if these factors contributed to the tau accumulation in vivo.

    View all comments by Laura Blair

  3. This is a really interesting study. These are small families but, for the first family, even though segregation is not perfect, this is most probably the causative mutation. The fact that the same mutation is seen in another non-related individual with the same phenotype also adds evidence to the causative role.

    This mutation is not present in HEX or TOPMed, and, as the authors mention, also not in gnomAD.

    It's not common to have this in-depth study of one mutation. The results show how valuable these can be: Different phenotypes can arise from mutations in the same gene and, at the same time, different mechanisms can lead to a same general outcome (neurodegeneration). This finding clearly indicates the need to fully study different mutations in the same gene and not assume all have the same effects on disease.

    View all comments by Rita Guerreiro

  4. This paper is a very interesting set of studies, which begin to reveal how a neurodegenerative tauopathy might emerge from a specific mutation in the AAA+ ATPase, VCP. VCP appears to antagonize tau aggregation, and the disease-linked VCP mutation appears to yield a VCP hypomorph with reduced activity.

    It remains uncertain why tau is specifically affected and not other neurodegenerative disease proteins, such as TDP-43. It will be of great interest to determine the precise mechanism by which VCP antagonizes tau aggregation and whether this activity might be harnessed therapeutically in other settings.

    View all comments by James Shorter

  5. This is a very well-performed study with very interesting findings, namely the identification of two families with a novel VCP mutation associated with a new type of vacuolar tauopathy.

    While such families might be very rare (at least I am not aware that I have seen such cases in our brain banks in the past), the finding with altered disaggregase activity of this VCP mutation leading to tau pathology is very exciting with impact for future drug development approaches in tauopathies in general.

    I find it particularly surprising that other proteins known to aggregate in a poly-ubiquitinated form such as α-synuclein or TDP-43 seem not to be affected by this VCP impairment (at least not resulting in aggregates by neuropathological analysis). While it would have been informative to include preparations of ubiquitinated forms of α-synuclein and TDP-43 in the assays, dissection of the potentially specific mode of action of VCP on tau aggregates will be very interesting in the future.

    View all comments by Manuela Neumann

  6. In this exciting work, Darwich et al. characterize an autosomal-dominant D395G mutation in the AAA+ ATPase chaperone VCP, which is associated with "vacuolar tauopathy" (VT), a novel form of tauopathy. Dr. Edward Lee's group provides compelling evidence that recombinant wild-type VCP and its cofactors UFD1L and NPLOC4 are capable of disaggregating Tau fibrils and that the VT-linked mutation exhibits decreased disaggregation activity. This correlated with a more severe Tau pathology in a mouse model carrying the D395G mutation, suggesting that reduced resolubilization of aggregated Tau causes VT.

    This is an intriguing finding, especially with respect to other cellular amyloid disaggregation systems. The cytosolic Hsp70 disaggregation machinery, consisting of the constitutively expressed Hsc70 and its co-chaperones, a class B J- domain protein and an Hsp110-type nucleotide exchange factor (NEF) (Gao et al., 2015; Nachman et al., 2020), or the proteasome (Cliffe et al., 2019), are also able to disentangle Tau fibrils, but at the cost of generating smaller fragments.

    For example, we have recently shown that amyloid Tau disaggregation by the Hsp70 chaperone system liberated both small oligomeric and monomeric species, which were able to induce self-propagating Tau species in a biosensor cell line (Nachman et al., 2020). This Hsp70 disaggregase could therefore have a similar function as the Hsp104-Hsp70 bichaperone system in yeast prion propagation and contribute to the accumulation of toxic amyloid conformers. In support of this idea, we were able to demonstrate that reduction of the essential co-chaperone Hsp-110 reduced the aggregation, toxicity and intercellular spreading of α-synuclein in a C. elegans model (Tittelmeier et al., 2020). Therefore, it would be very interesting to characterize the products of VCP-mediated Tau disaggregation regarding their seeding and spreading competence.

    The Hsp70 disaggregation machinery targets a broad spectrum of amyloid structures and showed activity against α-synuclein, all six Tau variants, and HTTExon1Q48 (Gao et al., 2015; Nachman et al., 2020; Scior et al., 2018). In contrast, VCP seems to have an extremely narrow substrate spectrum and to specifically target ubiquitinated Tau. Further investigation to determine the substrate spectrum of VCP, e.g., its effect on different Tau conformers, would be interesting. How is VCP embedded in the highly interconnected proteostasis network? Could other co-factors extend its substrate specificity? Is VCP-mediated disaggregation directly coupled to substrate degradation, and therefore more beneficial in vivo? And with regard to the severe vacuolization observed in these patients: Does VCP play a role in the intra- and/or intercellular transport of Tau?

    This excellent paper highlights the role of chaperone action in the etiology of neurodegenerative diseases. Future work will shed light on how VCP and other chaperone amyloid disaggregases contribute to disease progression in various proteinopathies, and it will be exciting to explore how such systems can be exploited as therapeutic targets.

    References:

    Cliffe R, Sang JC, Kundel F, Finley D, Klenerman D, Ye Y. Filamentous Aggregates Are Fragmented by the Proteasome Holoenzyme. Cell Rep. 2019 Feb 19;26(8):2140-2149.e3. PubMed.

    Gao X, Carroni M, Nussbaum-Krammer C, Mogk A, Nillegoda NB, Szlachcic A, Guilbride DL, Saibil HR, Mayer MP, Bukau B. Human Hsp70 Disaggregase Reverses Parkinson's-Linked α-Synuclein Amyloid Fibrils. Mol Cell. 2015 Sep 3;59(5):781-93. Epub 2015 Aug 20 PubMed.

    Nachman E, Wentink AS, Madiona K, Bousset L, Katsinelos T, Allinson K, Kampinga H, McEwan WA, Jahn TR, Melki R, Mogk A, Bukau B, Nussbaum-Krammer C. Disassembly of Tau fibrils by the human Hsp70 disaggregation machinery generates small seeding-competent species. J Biol Chem. 2020 Jul 10;295(28):9676-9690. Epub 2020 May 28 PubMed.

    Scior A, Buntru A, Arnsburg K, Ast A, Iburg M, Juenemann K, Pigazzini ML, Mlody B, Puchkov D, Priller J, Wanker EE, Prigione A, Kirstein J. Complete suppression of Htt fibrilization and disaggregation of Htt fibrils by a trimeric chaperone complex. EMBO J. 2018 Jan 17;37(2):282-299. Epub 2017 Dec 6 PubMed.

    Tittelmeier J, Sandhof CA, Ries HM, Druffel-Augustin S, Mogk A, Bukau B, Nussbaum-Krammer C. The HSP110/HSP70 disaggregation system generates spreading-competent toxic α-synuclein species. EMBO J. 2020 Jul 1;39(13):e103954. Epub 2020 May 25 PubMed.

    View all comments by Eliana Nachman

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  1. VCP Coding Mutation Causes a Tauopathy With Vacuoles