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

Yabe, Ichiro; Yaguchi, Hiroaki; Kato, Yasutaka; Miki, Yasuo; Takahashi, Hidehisa; Tanikawa, Satoshi; Shirai, Shinichi; Takahashi, Ikuko; Kimura, Mari; Hama, Yuka; Matsushima, Masaaki; Fujioka, Shinsuke; Kano, Takahiro; Watanabe, Masashi; Nakagawa, Shin; Kunieda, Y; Ikeda, Yoshio; Hasegawa, Masato; Nishihara, Hiroshi; Ohtsuka, Toshihisa; Tanaka, Shinya; Tsuboi, Yoshio; Hatakeyama, Susumi; Wakabayashi, Keiji; Sasaki, Hidenao

doi:10.1038/s41598-018-19198-0

Cited by 30 publications

(36 citation statements)

References 45 publications

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“… 21 In mice, BSN deficiency causes early onset severe epilepsy that is 50% lethal in the first 6 months of life. 22 To date, heterozygous BSN variants have been associated with an adult-onset progressive-supranuclear palsy-like syndrome 23 but an autosomal recessive form of this disease has not yet been described.…”

Section: Resultsmentioning

confidence: 99%

Infanticide vs. inherited cardiac arrhythmias

et al. 2020

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Aims In 2003, an Australian woman was convicted by a jury of smothering and killing her four children over a 10-year period. Each child died suddenly and unexpectedly during a sleep period, at ages ranging from 19 days to 18 months. In 2019 we were asked to investigate if a genetic cause could explain the deaths, as part of an inquiry into the mother’s convictions. Methods and results Whole genomes or exomes of the mother and her four children were sequenced. Functional analysis of a novel CALM2 variant was performed by measuring Ca2+-binding affinity, interaction with calcium channels and channel function. We found two children had a novel calmodulin variant (CALM2 G114R) that was inherited maternally. Three genes (CALM1-3) encode identical calmodulin proteins. A variant in the corresponding residue of CALM3 (G114W) was recently reported in a child who died suddenly at age 4 and a sibling who suffered a cardiac arrest at age 5. We show that CALM2 G114R impairs calmodulin's ability to bind calcium and regulate two pivotal calcium channels (CaV1.2 and RyR2) involved in cardiac excitation contraction coupling. The deleterious effects of G114R are similar to those produced by G114W and N98S, which are considered arrhythmogenic and cause sudden cardiac death in children. Conclusion A novel functional calmodulin variant (G114R) predicted to cause idiopathic ventricular fibrillation, catecholaminergic polymorphic ventricular tachycardia, or mild long QT syndrome was present in two children. A fatal arrhythmic event may have been triggered by their intercurrent infections. Thus, calmodulinopathy emerges as a reasonable explanation for a natural cause of their deaths.

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Section: Resultsmentioning

confidence: 99%

Infanticide vs. inherited cardiac arrhythmias

et al. 2020

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“…Bsn-deficient mice display systemic phenotypes including epilepsy and might be also prone to neurodegeneration [ 2 , 13 , 41 , 49 ]. To determine whether increased proteasome activity is a direct result of bassoon deficiency or a secondary effect of systemic phenotypes described in the animals deficient for Bsn expression, we tested chymotrypsin-, trypsin and caspase-like peptidase activities using fluorogenic specific peptidase substrates in cultured cortical neurons derived from newborn Bsn GT animals and their WT littermates.…”

Section: Resultsmentioning

confidence: 99%

“…Recently, mutations in BSN have been linked to human diseases associated with pathological protein aggregation. Bsn mutation found in the patients with familiar PSP-like syndrome significantly decreased the solubility and degradation of Bassoon in heterologous expression system and importantly, led to increased tau aggregation [ 49 ]. Moreover, highly upregulated Bsn expression and its accumulation in large aggregates in the somata of motoneurons, which is a characteristic hallmark of the inflammation-induced degeneration, were found in spinal cord samples from patients with multiple sclerosis (MS) and from the respective disease mouse model, the experimental autoimmune encephalomyelitis (EAE).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, two recent clinical reports further support a key role of Bsn in the regulation of neuronal proteostasis. In the first study, homozygous missense mutations in BSN has been linked with familiar and sporadic progressive supranuclear palsy (PSP)-like syndrome associated with tauopathy [ 49 ]. In the second, Bsn has been identified as a constituent of toxic accumulates in the somata of motoneurons in mice and patients with multiple sclerosis [ 41 ].…”

Section: Introductionmentioning

confidence: 99%

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Bassoon inhibits proteasome activity via interaction with PSMB4

Montenegro-Venegas

Fieńko

Anni

et al. 2020

Cell. Mol. Life Sci.

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Proteasomes are protein complexes that mediate controlled degradation of damaged or unneeded cellular proteins. In neurons, proteasome regulates synaptic function and its dysfunction has been linked to neurodegeneration and neuronal cell death. However, endogenous mechanisms controlling proteasomal activity are insufficiently understood. Here, we describe a novel interaction between presynaptic scaffolding protein bassoon and PSMB4, a β subunit of the 20S core proteasome. Expression of bassoon fragments that interact with PSMB4 in cell lines or in primary neurons attenuates all endopeptidase activities of cellular proteasome and induces accumulation of several classes of ubiquitinated and non-ubiquitinated substrates of the proteasome. Importantly, these effects are distinct from the previously reported impact of bassoon on ubiquitination and autophagy and might rely on a steric interference with the assembly of the 20S proteasome core. In line with a negative regulatory role of bassoon on endogenous proteasome we found increased proteasomal activity in the synaptic fractions prepared from brains of bassoon knock-out mice. Finally, increased activity of proteasome and lower expression levels of synaptic substrates of proteasome could be largely normalized upon expression of PSMB4-interacting fragments of bassoon in neurons derived from bassoon deficient mice. Collectively, we propose that bassoon interacts directly with proteasome to control its activity at presynapse and thereby it contributes to a compartment-specific regulation of neuronal protein homeostasis. These findings provide a mechanistic explanation for the recently described link of bassoon to human diseases associated with pathological protein aggregation. Graphic Abstract Presynaptic cytomatrix protein bassoon (Bsn) interacts with PSMB4, the β7 subunit of 20S core proteasome, via three independent interaction interfaces. Bsn inhibits proteasomal proteolytic activity and degradation of different classes of proteasomal substrates presumably due to steric interference with the assembly of 20S core of proteasome. Upon Bsn deletion in neurons, presynaptic substrates of the proteasome are depleted, which can be reversed upon expression of PSMB4-interacting interfaces of Bsn. Taken together, bsn controls the degree of proteasome degradation within the presynaptic compartment and thus, contributes to the regulation of synaptic proteome

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“…Although PSP is generally recognized as a sporadic syndrome, there are familial forms of PSP [ 13–15 ] and few pedigrees with PSP-like phenotypes [ 16, 17 ], and a pattern of autosomal dominant inheritance has been proposed [ 14, 15 ]. A case-control study has observed more first-degree relatives with parkinsonism or dementia in patients with PSP than in controls, demonstrating familial aggregation in PSP [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Genetics of Progressive Supranuclear Palsy: A Review

Wen

Zhou

Jiao

et al. 2021

JPD

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Progressive supranuclear palsy (PSP) is an atypical parkinsonism with prominent 4R-tau neuropathology, and the classical clinical phenotype is characterized by vertical supranuclear gaze palsy, unprovoked falls, akinetic-rigid syndrome and cognitive decline. Though PSP is generally regarded as sporadic, there is increasing evidence suggesting that a series of common and rare genetic variants impact on sporadic and familial forms of PSP. To date, more than 10 genes have been reported to show a potential association with PSP. Among these genes, the microtubule-associated protein tau (MAPT) is the risk locus with the strongest effect size on sporadic PSP in the case-control genome-wide association studies (GWAS). Additionally, MAPT mutations are the most common cause of familial PSP while the leucine-rich repeat kinase 2 (LRRK2) is a rare monogenic cause of PSP, and several other gene mutations may mimic the PSP phenotype, like the dynactin subunit 1 (DCTN1). In total, 15 MAPT mutations have been identified in cases with PSP, and the mean age at onset is much earlier than in cases carrying LRRK2 or DCTN1 mutations. GWAS have further identified several risk loci of PSP, proposing molecular pathways related to PSP. The present review focused on genetic studies on PSP and summarized genetic factors of PSP, which may help to elucidate the underlying pathogenesis and provide new perspectives for therapeutic strategies.

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

Cited by 30 publications

References 45 publications

Infanticide vs. inherited cardiac arrhythmias

Infanticide vs. inherited cardiac arrhythmias

Bassoon inhibits proteasome activity via interaction with PSMB4

Genetics of Progressive Supranuclear Palsy: A Review

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