Mutations in bassoon in individuals with familial and sporadic progressive supranuclear palsy-like syndrome

Yabe, Ichiro; Yaguchi, Hiroaki; Kato, Yasutaka; Miki, Yasuo; Takahashi, Hiroyuki; Tanikawa, Satoshi; Shirai, Shinichi; Takahashi, Ikuko; Fujioka, Shinsuke; Watanabe, Mika; Nakagawa, Souichi; Kunieda, Y; Ikeda, Yoshio; Hasegawa, Masato; Nishihara, Hiroshi; Tanaka, Shinya; Tsuboi, Yoshio; Hatakeyama, Susumi; Wakabayashi, Keiji; Sasaki, Hidenao

doi:10.1016/j.jns.2017.08.2962

Cited by 2 publications

(6 citation statements)

References 19 publications

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“…To date, there are 98,622 subjects for whom both whole genome sequencing and clinical data are available. Half of the participants (47,897) are unrelated and of European ancestry.…”

Section: Association Of Bmi-correlated Traits In Bsnmentioning

confidence: 99%

Predicted loss of function alleles in Bassoon (BSN) are associated with obesity

Zhu

LeDuc

Fennoy

et al. 2023

Preprint

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Bassoon (BSN) is a component of a hetero-dimeric presynaptic cytomatrix protein that orchestrates neurotransmitter release with Piccolo (PCLO) from glutamatergic neurons throughout the brain. Heterozygous missense variants in BSN have previously been associated with neurodegenerative disorders in humans. We performed an exome-wide association analysis of ultra-rare variants in about 140,000 unrelated individuals from the UK Biobank to search for new genes associated with obesity. We found that rare heterozygous predicted loss of function (pLoF) variants in BSN are associated with higher BMI with log10-p value of 11.78 in the UK biobank cohort. The association was replicated in the All of Us whole genome sequencing data. Additionally, we have identified two individuals (one of whom has a de novo variant) with a heterozygous pLoF variant in a cohort of early onset or extreme obesity at Columbia University. Like the individuals identified in the UKBB and All of us Cohorts, these individuals have no history of neurobehavioral or cognitive disability. Heterozygosity for pLoF BSN variants constitutes a new etiology for obesity.

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“…To date, there are 98,622 subjects for whom both whole genome sequencing and clinical data are available. Half of the participants (47,897) are unrelated and of European ancestry.…”

Section: Association Of Bmi-correlated Traits In Bsnmentioning

confidence: 99%

Predicted loss of function alleles in Bassoon (BSN) are associated with obesity

Zhu

LeDuc

Fennoy

et al. 2023

Preprint

View full text Add to dashboard Cite

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“…Little is known about the importance of BSN in tau pathology and neurodegeneration. The strongest evidence linking BSN with tau pathology was published in 2018, revealing four missense mutations in the BSN gene (p.Pro3866Ala) and aggregation of three-repeat and four-repeat tau in patients 32 . Another study revealed increased BSN expression in patients with multiple system atrophy 33 , a neurodegenerative disease characterized by the aggregation of alpha-synuclein and tau protein 43 .…”

Section: Discussionmentioning

confidence: 99%

“…A third possibility is that a tau conformer with seeding activity utilizes the presynaptic vesicle fusion machinery for neuronal release, as suggested for physiological tau 21 , through aberrant protein interactions. In our study, we focused on the presynaptic protein BSN as a new interactor of the tau seed, considering the strong genetic link between BSN mutation and human tauopathies 32 . Nevertheless, further studies are necessary to determine the relevance of the presynaptic machinery in tau-seed propagation and overall pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…From this comparison, we identified BSN, a scaffolding protein of the presynaptic active zone involved in regulating synaptic neurotransmitter release 22 , presynaptic proteostasis and autophagy [29][30][31] , as a significant interactor of the tau seed. Surprisingly, missense mutations in the BSN gene have recently been identified in a family with pathological aggregation of 3R/4R tau 32 . Additionally, BSN expression is increased in patients with multiple system atrophy 33 and BSN accumulates in patients with multiple sclerosis 34 .…”

Section: Articlementioning

confidence: 99%

“…We overexpressed human BSN in two transgenic Drosophila melanogaster lines to investigate the effects of BSN upregulation in vivo, one line overexpressing WT BSN and the other overexpressing BSN harboring the p.Pro3866Ala mutation, recently identified in patients with pathological aggregation of 3R/4R tau 32 (Extended Data Fig. 4h).…”

Section: Bsn Protein Interacts With a High-molecular-weight Tau Seedmentioning

confidence: 99%

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Bassoon contributes to tau-seed propagation and neurotoxicity

et al. 2022

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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 supranuclear palsy postmortem samples. We show that BSN exacerbates tau seeding and toxicity in both mouse and Drosophila models for tauopathy, and that BSN downregulation decreases tau spreading and overall disease pathology, rescuing synaptic and behavioral impairments and reducing brain atrophy. Our findings improve the understanding of how tau seeds can be stabilized by interactors such as BSN. Inhibiting tau-seed interactions is a potential new therapeutic approach for neurodegenerative tauopathies.

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Mutations in bassoon in individuals with familial and sporadic progressive supranuclear palsy-like syndrome

Cited by 2 publications

References 19 publications

Predicted loss of function alleles in Bassoon (BSN) are associated with obesity

Predicted loss of function alleles in Bassoon (BSN) are associated with obesity

Bassoon contributes to tau-seed propagation and neurotoxicity

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