更新于：2024-05-01

TTBK2

tau tubulin kinase 2

更新于：2024-05-01

基本信息

别名

KIAA0847、SCA11、spinocerebellar ataxia 11

+ [3]

简介

Serine/threonine kinase that acts as a key regulator of ciliogenesis: controls the initiation of ciliogenesis by binding to the distal end of the basal body and promoting the removal of CCP110, which caps the mother centriole, leading to the recruitment of IFT proteins, which build the ciliary axoneme. Has some substrate preference for proteins that are already phosphorylated on a Tyr residue at the +2 position relative to the phosphorylation site. Able to phosphorylate tau on serines in vitro (PubMed:23141541). Phosphorylates MPHOSPH9 which promotes its ubiquitination and proteasomal degradation, loss of MPHOSPH9 facilitates the removal of the CP110-CEP97 complex (a negative regulator of ciliogenesis) from the mother centrioles, promoting the initiation of ciliogenesis (PubMed:30375385).

关联

100 项与 TTBK2 相关的临床结果

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100 项与 TTBK2 相关的转化医学

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0 项与 TTBK2 相关的专利（医药）

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项与 TTBK2 相关的文献（医药）

2023-12-05·Cell death & disease

Phosphorylation of MIF by PIP4K2a is necessary for cilia biogenesis.

Article

作者: Lu Zhang ; Hongbing Zhang ; Ewud Agborbesong ; Julie Xia Zhou ; Xiaogang Li

Primary cilia are microtubule-based organelles that play important roles in development and tissue homeostasis. Macrophage migration inhibitory factor (MIF) has long been recognized as a secreted cytokine in the pathogenesis of various human diseases, including cancer and autosomal dominant polycystic kidney disease (ADPKD). Unlike other cytokines, unique functional characteristics of intracellular MIF have emerged. In this study, we show that MIF is localized and formed a ring like structure at the proximal end of centrioles, where it regulates cilia biogenesis through affecting 1) the recruitment of TTBK2 to basal body and the removal of CP110 from mother centriole, 2) the accumulation of CEP290 at centriolar satellites, and 3) the trafficking of intraflagellar transport (IFT) related proteins. We also show that MIF functions as a novel transcriptional factor to regulate the expression of genes related to ciliogenesis via binding on the promotors of those genes. MIF also binds chromatin and regulates transcription of genes involved in diverse homeostatic signaling pathways. We identify phosphatidylinositol-5-phosphate 4-kinase type 2 alpha (PIP4K2a) as an upstream regulator of MIF, which interacts with and phosphorylates MIF at S91 to increase its interaction with 14-3-3ζ, resulting in its nuclear translocation and transcription regulation. This study suggests that MIF is a key player in cilia biogenesis and a novel transcriptional regulator in homeostasis, which forward our understanding of how MIF is able to carry out several nonoverlapping functions.

2023-10-19·Acta neuropathologica communications

Antisense oligonucleotide-based targeting of Tau-tubulin kinase 1 prevents hippocampal accumulation of phosphorylated tau in PS19 tauopathy mice.

Article

作者: Kayo Yukawa ; Satomi Yamamoto-Mcguire ; Louis Cafaro ; Christine Hong ; Fredrik Kamme ; Tsuneya Ikezu ; Seiko Ikezu

Tau tubulin kinase-1 (TTBK1), a neuron-specific tau kinase, is highly expressed in the entorhinal cortex and hippocampal regions, where early tau pathology evolves in Alzheimer's disease (AD). The protein expression level of TTBK1 is elevated in the cortex brain tissues with AD patients compared to the control subjects. We therefore hypothesized that antisense oligonucleotide (ASO) based targeting Ttbk1 could prevent the accumulation of phosphorylated tau, thereby delaying the development of tau pathology in AD. Here we show that in vivo administration of ASO targeting mouse Ttbk1 (ASO-Ttbk1) specifically suppressed the expression of Ttbk1 without affecting Ttbk2 expression in the temporal cortex of PS19 tau transgenic mice. Central administration of ASO-Ttbk1 in PS19 mice significantly reduced the expression level of representative phosphor-tau epitopes relevant to AD at 8 weeks post-dose, including pT231, pT181, and pS396 in the sarkosyl soluble and insoluble fractions isolated from hippocampal tissues as determined by ELISA and pS422 in soluble fractions as determined by western blotting. Immunofluorescence demonstrated that ASO-Ttbk1 significantly reduced pS422 phosphorylated tau intensity in mossy fibers region of the dentate gyrus in PS19 mice. RNA-sequence analysis of the temporal cortex tissue revealed significant enrichment of interferon-gamma and complement pathways and increased expression of antigen presenting molecules (Cd86, Cd74, and H2-Aa) in PS19 mice treated with ASO-Ttbk1, suggesting its potential effect on microglial phenotype although neurotoxic effect was absent. These data suggest that TTBK1 is an attractive therapeutic target to suppress TTBK1 without compromising TTBK2 expression and pathological tau phosphorylation in the early stages of AD.

2023-10-17·Cerebellum (London, England)

A Novel TTBK2 Mutation in a Chinese Pedigree with Spinocerebellar Ataxia 11.

Article

作者: Yin-Qian Lu ; Jian-Min Chen ; Ya-Li Huang ; Zhang-Yu Zou

Spinocerebellar ataxia type 11 (SCA11) is a rare disease and the tau tubulin kinase 2 (TTBK2) gene was the causative gene. To date, only six SCA11 families have been reported. Here, we reported a Chinese SCA11 pedigree with cerebellar ataxia. Both patients in the family demonstrated typical clinical features of cerebellar ataxia and cerebellar atrophy on brain MRI. A novel heterozygous duplication mutation (c.1211_1217dupAGGAGAA) of the TTBK2 gene was identified in the proband using whole-exome sequencing (WES), which resulted in a frameshift mutation and formed a premature stop codon (p. N406Kfs*47). The mutation was detected in the proband's affected brother, and his unaffected mother, who with a lower percentage of the mutation and considered as an asymptomatic mutation carrier. Our study delineated the genotypic spectrum of SCA11.

项与 TTBK2 相关的新闻（医药）

2024-02-29

·PRNewswire

BioArctic: Latest data on lecanemab to be presented at the 2024 AD/PD™ congress

STOCKHOLM, Feb. 29, 2024 /PRNewswire/ -- BioArctic AB (publ) (STO: BIOA-B) today announced that the company and its partner Eisai will present new data on lecanemab (brand name: Leqembi®) at the 2024 International Conference on Alzheimer's and Parkinson's Diseases and related neurological disorders (AD/PD™), to be held in Lisbon, Portugal and virtually, March 5-9. In total, lecanemab will be featured in six presentations, including an oral presentation by BioArctic's founder Professor Lars Lannfelt. Lecanemab is the result of a long-standing collaboration between BioArctic and Eisai, and the anti-amyloid beta (Aβ) protofibril antibody was originally developed by BioArctic based on the work of Professor Lars Lannfelt and his discovery of the Arctic mutation in Alzheimer's disease. At AD/PD, BioArctic will present one oral presentation and one poster on lecanemab, both focused on the binding properties of lecanemab to various types of Aβ of lecanemab compared to several other Aβ antibodies. The company will also have two other posters related to Alzheimer's disease. In addition to BioArctic's presentations, Eisai will present four oral presentations on lecanemab results. From the Phase 3 Clarity AD study in early Alzheimer's disease[1] with confirmed brain Aβ accumulation, data will include the effect of lecanemab treatment on tau[2] accumulation in whole brain regions, and outcomes of long-term efficacy of lecanemab. In addition, the differences in the binding properties of multiple anti-amyloid (Aβ) antibodies to various types of Aβ and other data will be presented. Eisai will also sponsor a symposium featuring three prominent clinical experts in the field of Alzheimer's disease, Dr. Jeffrey Cummings, Dr. Robert Perneczky and Dr. Miia Kivipelto. Dr. Jeffrey Cummings will chair the symposium, and provide an overview of meaningful benefits, including clinical meaningfulness and the evolution of approaches for the clinical study of Alzheimer's disease. Dr. Robert Perneczky will discuss how to assess meaningful benefits of treatments in development for Alzheimer's disease. Dr. Miia Kivipelto's presentation will provide new statistical methods to measure meaningful benefits and address various stakeholder perspectives. Furthermore, Eisai's Chief Clinical Officer, Lynn Kramer, M.D., will give a plenary presentation titled "Novel approaches to clinical development and the future potential of simulated placebo" on March 7 at the "Aβ TARGETING THERAPIES IN AD 1" session. Eisai serves as the lead of Leqembi development and regulatory submissions globally with both Eisai and Biogen co-commercializing and co-promoting the product and Eisai having final decision-making authority. BioArctic has the right to commercialize lecanemab in the Nordic region, pending European approval, and currently Eisai and BioArctic are preparing for a joint commercialization in the region. Presentations by BioArctic and Eisai Oral presentations Poster presentations Eisai-Sponsored Symposium Plenary presentation This release discusses investigational uses of an agent in development and is not intended to convey conclusions about efficacy or safety. There is no guarantee that such investigational agents will successfully complete clinical development or gain health authority approval. The information was released for public disclosure, through the agency of the contact persons below, on February 29, 2024, at 08.00 a.m. CET. For further information, please contact: Oskar Bosson, VP Communications and IR E-mail: [email protected] Phone: +46 70 410 71 80 Jiang Millington, Director Corporate Communication and Social Media E-mail: [email protected] Phone: +46 79 33 99 166 About lecanemab (generic name, U.S., Japan and China brand name: Leqembi®) Lecanemab is the result of a strategic research alliance between BioArctic and Eisai. Lecanemab is a humanized immunoglobulin gamma 1 (IgG1) monoclonal antibody directed against aggregated soluble (protofibril) and insoluble forms of amyloid-beta (Aβ). In the U.S., Leqembi was granted traditional approval by the US Food and Drug Administration (FDA) on July 6, 2023. Leqembi is indicated as a disease-modifying treatment for Alzheimer's disease (AD) in the US. Treatment with Leqembi should be initiated in patients with mild cognitive impairment (MCI) or mild dementia stage of disease, the population in which treatment was initiated in clinical trials. Please see full U.S. Prescribing Information. In Japan, Eisai received approval from the Ministry of Health, Labour and Welfare (MHLW) on September 25, 2023, to manufacture and market lecanemab as a treatment for slowing progression of MCI and mild dementia due to AD. Furthermore, in China, Leqembi was approved by the National Medical Products Administration (NMPA) as a treatment of MCI due to AD and mild AD dementia in January 2024. Eisai has also submitted applications for approval of lecanemab in 14 different countries, including EU, Canada and Great Britain. Eisai has completed a lecanemab subcutaneous bioavailability study, and subcutaneous dosing is currently being evaluated in the Clarity AD (Study 301) open-label extension (OLE) study. A maintenance dosing regimen has been evaluated as part of the Phase 2b study (Study 201). Since July 2020 Eisai's Phase 3 clinical study (AHEAD 3-45) for individuals with preclinical AD, meaning they are clinically normal and have intermediate or elevated levels of amyloid in their brains, is ongoing. AHEAD 3-45 is conducted as a public-private partnership between the Alzheimer's Clinical Trial Consortium that provides the infrastructure for academic clinical trials in AD and related dementias in the U.S, funded by the National Institute on Aging, part of the National Institutes of Health and Eisai. Since January 2022, the Tau NexGen clinical study for Dominantly Inherited AD (DIAD), that is conducted by Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU), led by Washington University School of Medicine in St. Louis, is ongoing and includes lecanemab as the backbone anti-amyloid therapy. About the collaboration between BioArctic and Eisai Since 2005, BioArctic has a long-term collaboration with Eisai regarding the development and commercialization of drugs for the treatment of Alzheimer's disease. The most important agreements are the Development and Commercialization Agreement for the lecanemab antibody, which was signed 2007, and the Development and Commercialization agreement for the antibody Leqembi back-up for Alzheimer's disease, which was signed 2015. In 2014, Eisai and Biogen entered into a joint development and commercialization agreement for lecanemab. Eisai is responsible for the clinical development, application for market approval and commercialization of the products for Alzheimer's disease. BioArctic has the right to commercialize lecanemab in the Nordic region under certain conditions and is currently preparing for commercialization in the Nordics together with Eisai. BioArctic has no development costs for lecanemab in Alzheimer's disease and is entitled to payments in connection with regulatory approvals, and sales milestones as well as royalties on global sales. About BioArctic AB BioArctic AB (publ) is a Swedish research-based biopharma company focusing on innovative treatments that can delay or stop the progression of neurodegenerative diseases. The company invented Leqembi® (lecanemab) – the world's first drug proven to slow the progression of the disease and reduce cognitive impairment in early Alzheimer's disease. Leqembi has been developed together with BioArctic's partner Eisai, who are responsible for regulatory interactions and commercialization globally. In addition to Leqembi, BioArctic has a broad research portfolio with antibodies against Parkinson's disease and ALS as well as additional projects against Alzheimer's disease. Several of the projects utilize the company's proprietary BrainTransporter™ technology, which has the potential to actively transport antibodies across the blood-brain barrier to enhance the efficacy of the treatment. BioArctic's B share (BIOA B) is listed on Nasdaq Stockholm Large Cap. For further information, please visit . [1] Early Alzheimer's disease includes mild cognitive impairment (MCI) due to Alzheimer's disease and mild Alzheimer's disease [2] A protein that aggregates intracellularly in nerve cells in Alzheimer's disease, disrupting both the function and survival of the cell. Tau levels can be measured in plasma, cerebrospinal fluid, and with a positron camera (PET). The following files are available for download:

上市批准临床3期临床2期引进/卖出