Dataset Information

Bassoon contributes to tau-seed neurotoxicity and propagation.

ABSTRACT: Tau aggregates are critical pathological features of Alzheimer’s disease (AD) and other tauopathies. Growing evidence suggests that soluble tau aggregates trigger neurodegenerative phenotypes. However, the nature of the tau species and interactors involved in its aggregation and spreading remains unclear. By using size exclusion chromatography, mass spectrometry, and bioinformatic analysis, we identified Bassoon protein (BSN) as a significant tau interactor in PS19 mice, as well as in human AD and PSP cases. We also found that overexpression of BSN triggers the aggregation of tau and increase the tau seeding activity in vitro, and also exacerbates the degenerative phenotype in a Fly model for tauopathy. Knockdown of BSN significantly reduced tau spreading in PS19 mouse brains and destabilized the tau aggregates, leading to a reduction in the tau pathology in this model. Furthermore, BSN downregulation was able to restore the neurodegenerative phenotype in PS19 mice, observed in electrophysiology and behavioral tests. Our results identify BSN as a key interactor of tau spread and aggregation in the brain, and therefore a potential target for the treatment of diseases that involve tau spread and aggregation.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Aruna Wijeratne

LAB HEAD: Cristian Lasagna-Reeves

PROVIDER: PXD027451 | Pride | 2023-03-11

REPOSITORIES: Pride

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Publications

Bassoon contributes to tau-seed propagation and neurotoxicity.

Martinez Pablo P Patel Henika H You Yanwen Y Jury Nur N Perkins Abigail A Lee-Gosselin Audrey A Taylor Xavier X You Yingjian Y Viana Di Prisco Gonzalo G Huang Xiaoqing X Dutta Sayan S Wijeratne Aruna B AB Redding-Ochoa Javier J Shahid Syed Salman SS Codocedo Juan F JF Min Sehong S Landreth Gary E GE Mosley Amber L AL Wu Yu-Chien YC McKinzie David L DL Rochet Jean-Christophe JC Zhang Jie J Atwood Brady K BK Troncoso Juan J Lasagna-Reeves Cristian A CA

Nature neuroscience 20221107 12

Tau aggregation is a defining histopathological feature of Alzheimer's disease and other tauopathies. However, the cellular mechanisms involved in tau propagation remain unclear. Here, we performed an unbiased quantitative proteomic study to identify proteins that specifically interact with this tau seed. We identified Bassoon (BSN), a presynaptic scaffolding protein, as an interactor of the tau seed isolated from a mouse model of tauopathy, and from Alzheimer's disease and progressive supranucl ...[more]

PMID: 36344699

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Project description:Transposable elements have the potential to act as controlling elements to influence the expression of genes. The current paradigm suggests that heterochromatic silencing can spread beyond the borders of the transposable element and influence the chromatin state of neighboring low-copy sequences. This would allow transposable elements to condition obligatory or facilitated epialleles and act as controlling elements. The maize genome contains numerous families of class I transposable elements (retrotransposons) that are present in moderate to high copy numbers and many are found in regions near genes which provides an opportunity to test whether the spreading of heterochromatin from retrotransposons is prevalent. We have investigated the extent of heterochromatin spreading into flanking DNA around each family of retrotransposons through profiling of DNA methylation and di-methylation of lysine 9 of histone 3 (H3K9me2) in low-copy regions of the maize genome. The effects of different retrotransposon families on local chromatin are highly variable. Some LTR families exhibit enrichment of heterochromatic marks within 800-1200 base pairs of the insertion site while other families have very little evidence for spreading of heterochromatic marks. The analysis of chromatin state in genotypes that lack specific insertions suggests that the adjacent heterochromatin results from spreading of silencing rather than insertion-site preferences. Genes that are located near elements that exhibit spreading of heterochromatin tend to be expressed at lower levels than other genes. Our findings suggest that a subset of LTR retrotransposon families may act as controlling elements influencing neighboring sequences while the majority of elements have little effect on flanking sequences Transposable elements comprise a substantial portion of many eukaryotic genomes. These mobile fragments of DNA can result in mutations through insertions into genes but may also affect the regulation of genes they insert near. There is evidence that the majority of transposable elements are epigenetically silenced and in some cases this silencing may affect neighboring sequences. However, evolutionary theory would predict that there would be selective pressures for transposable elements to limit their effects on neighboring genes. The maize genome has a complex organization with many genes flanked by retrotransposons. We profiled the spread of heterochromatin from the retrotransposons into nearby low copy sequences for 150 high copy retrotransposon families. While the manymajority of retrotransposons exhibit little to no spreading of heterochromatin there are a small number ofsome retrotransposon families that influence the chromatin state of surrounding regions. The families may represent bad “neighbors” that spread heterochromatin and influence nearby genes. 6 total samples: 3 replicates of B73 H3k9 and 3 replicates of Mo17 H3k9 3 total samples: mop1 mutant, b73.zmet2 (zmet2.m1 mutant in B73 background) and mo17.zmet2 (zmet2.m1 mutant in Mo17 background)

Dataset Information

Bassoon contributes to tau-seed neurotoxicity and propagation.

Publications

Bassoon contributes to tau-seed propagation and neurotoxicity.

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