Martinez P, Patel H, You Y, Jury N, Perkins A, Lee-Gosselin A, Taylor X, You Y, Viana Di Prisco G, Huang X, Dutta S, Wijeratne AB, Redding-Ochoa J, Shahid SS, Codocedo JF, Min S, Landreth GE, Mosley AL, Wu YC, McKinzie DL, Rochet JC, Zhang J, Atwood BK, Troncoso J, Lasagna-Reeves CA. Bassoon contributes to tau-seed propagation and neurotoxicity. Nat Neurosci. 2022 Dec;25(12):1597-1607. Epub 2022 Nov 7 PubMed.

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  1. Although previous interactome-based studies have identified several tau interactors, interactomes of seed-competent tau, and how they influence tau propagation, are unknown. This interesting paper by Martinez et al. provides compelling evidence that a presynaptic scaffolding protein, Bassoon, interacts with tau seed and influences tau pathology and neurotoxicity, as determined utilizing cellular and mouse models. Our main takeaway from this study is that interaction of tau and its binding proteins at a specific subcellular compartment (i.e., presynapses) could significantly impact tau pathology progression.

    The authors suggested several possibilities ways Bassoon drives tau propagation, which involve altered stability, resistance to degradation, or altered neuronal release through aberrant protein interactions. Given that simple overexpression of Bassoon impacts insoluble tau deposition in non-neuronal HEK293 cells, a mechanism unrelated to synaptic vesicle release might play a role. Altered susceptibility toward proteinase K digestion also suggests that Bassoon influences the structure of tau aggregates.

    Another question is whether Bassoon specifically influences tau deposition or impacts other neurodegenerative proteins, such as α-synuclein, that propagate between neurons. Investigations into those mechanisms would significantly improve our understanding of the propagation of pathogenic proteins.

    View all comments by Takeshi Iwatsubo

  2. This was a rigorous and important study where the authors sought to identify proteins that specifically interact with tau seeds using co-immunoprecipitation coupled to mass spectrometry. To achieve this goal, they first performed size exclusion chromatography (SEC) from the PS19 mouse model to pinpoint fractions that induce robust tau seeding in the tau HEK-FRET biosensor cell line. They found a high molecular weight fraction, which contained only 5 percent of total tau, was most robust for seeding in the cell model. This was an important biochemical fractionation step, because it helped prioritize which fraction to perform the tau co-IP and MS. Most studies have immunoprecipitated tau from total tissue lysates, whereas the authors were specifically trying to enrich proteins that interact with tau seeds. Following MS analysis, they ultimately identified Bassoon (BSN) as one such interactor and prioritized BSN based on genetics and target rankings in the AMP-AD consortium. The interaction between BSN and tau was further validated in human postmortem AD and PSP tissues.

    A main takeaway is that Bassoon, and potentially other presynaptic scaffolding proteins, could act to enhance tau seeding and toxicity in tauopathies. Notably, other presynaptic proteins (Synaptotagmin-1) that interact with tau seeds in this study have also been reported as CSF biomarkers for AD analogous to tau (see citations below). This suggests potentially shared mechanisms in their activity or function (Öhrfelt et al., 2016; Lleó et al., 2019).

    Missense mutations in BSN were recently identified in familial and sporadic progressive supranuclear palsy-like syndrome (Yabe et al., 2028). This genetic link, combined with the fact that BSN enhances tau seeding, as shown in this study, provides strong rationale for BSN as a therapeutic target in tauopathies.

    References:

    Öhrfelt A, Brinkmalm A, Dumurgier J, Brinkmalm G, Hansson O, Zetterberg H, Bouaziz-Amar E, Hugon J, Paquet C, Blennow K. The pre-synaptic vesicle protein synaptotagmin is a novel biomarker for Alzheimer's disease. Alzheimers Res Ther. 2016 Oct 3;8(1):41. PubMed.

    Lleó A, Núñez-Llaves R, Alcolea D, Chiva C, Balateu-Paños D, Colom-Cadena M, Gomez-Giro G, Muñoz L, Querol-Vilaseca M, Pegueroles J, Rami L, Lladó A, Molinuevo JL, Tainta M, Clarimón J, Spires-Jones T, Blesa R, Fortea J, Martínez-Lage P, Sánchez-Valle R, Sabidó E, Bayés À, Belbin O. Changes in Synaptic Proteins Precede Neurodegeneration Markers in Preclinical Alzheimer's Disease Cerebrospinal Fluid. Mol Cell Proteomics. 2019 Mar;18(3):546-560. Epub 2019 Jan 3 PubMed.

    Yabe I, Yaguchi H, Kato Y, Miki Y, Takahashi H, Tanikawa S, Shirai S, Takahashi I, Kimura M, Hama Y, Matsushima M, Fujioka S, Kano T, Watanabe M, Nakagawa S, Kunieda Y, Ikeda Y, Hasegawa M, Nishihara H, Ohtsuka T, Tanaka S, Tsuboi Y, Hatakeyama S, Wakabayashi K, Sasaki H. Mutations in bassoon in individuals with familial and sporadic progressive supranuclear palsy-like syndrome. Sci Rep. 2018 Jan 16;8(1):819. PubMed.

    View all comments by Nicholas Seyfried

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