Role of viral infections in potassium channel-related cerebellar ataxia

病毒感染在钾通道相关小脑共济失调中的作用

• 批准号: 10640848
• 负责人: AKIKO IWASAKI
• 金额: $ 54.02万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-18 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10640848
• 关键词: Adaptor Signaling Protein; Affect; Aftercare; Aging; Animal Model; Animals; Apoptotic; Ataxia; Atrophic; Autophagocytosis; Binding; Biochemical; Biological; Biological Assay; Birth; Brain; Cell Death; Cell Survival; Cell membrane; Cell model; Cell physiology; Cells; Cerebellar Ataxia; Cerebellar degeneration; Cerebellum; Cessation of life; Co-Immunoprecipitations; Couples; DNA Sequence Alteration; Data; Defense Mechanisms; Dependence; Development; Developmental Delay Disorders; Disease; Distal; Electroencephalography; Enzymes; Etiology; Exposure to; Family; Functional disorder; Genes; Genetic; Genital; Genitalia; Goals; Healthcare Systems; Human; IFNAR1 gene; Immune; Impairment; Individual; Inflammation; Influenza A virus; Interferon Type I; Interferons; Ion Channel; Ions; Kinetics; Lead; Life; Light; Link; Locomotion; Longevity; Measurement; Molecular; Molecular Probes; Mucous Membrane; Multivesicular Body; Mus; Mutant Strains Mice; Mutation; Neurobiology; Neurodegenerative Disorders; Neurons; Onset of illness; Patch-Clamp Techniques; Pathway interactions; Persons; Point Mutation; Potassium Channel; Predisposition; Property; Proteins; Purkinje Cells; Recombinant Interferon; Respiratory System; Role; Signal Induction; Signal Pathway; Signal Transduction; Simplexvirus; Site-Directed Mutagenesis; Slice; Small Interfering RNA; Spinocerebellar Ataxias; Symptoms; TANK-binding kinase 1; Testing; Toll-like receptors; Transfection; Vesicular stomatitis Indiana virus; Viral; Virus Diseases; autosome; cellular pathology; cytokine; disease-causing mutation; early onset; effective therapy; experimental study; middle age; motor disorder; motor symptom; mutant; neuronal excitability; novel therapeutic intervention; pathogen; premature; response; stressor; synergism; type I interferon receptor; voltage

Cerebellar ataxia is a progressive neurodegenerative disease with major impact on the daily life of affected people, their families, and, on the health care system. There is no cure for cerebellar ataxia regardless of its origin. There is no effective treatment to slow the progression of symptoms that frequently lead to premature death. Ion channels have been implicated in the etiology of several form of cerebellar ataxia. For example, specific mutations in KCNC3, the gene encoding the Kv3.3 channel, such as the G592R point mutation, have been identified as the underlying genetic cause of late-onset spinocerebellar ataxia. Despite of these developments, there is no understanding of why late-onset cerebellar ataxias emerge in some but not all subjects with genetic mutations. There is also great variability in when during the lifespan of the affected subjects the symptoms emerge. Based on our unexpected preliminary observations, we hypothesize that disease onset in genetically vulnerable subjects is determined by host-pathogen interactions with particular emphasis on viral infections. Specifically, we assert that the synergistic activation of an intracellular signaling pathway that is targeted by both the mutant potassium channel and by viral defense mechanisms, impairs cellular function and results in the death of Purkinje cells. Our hypothesis and preliminary data challenge contemporary views on the etiology of cerebellar ataxia with implications for novel therapeutic strategies. We will test our hypothesis using cellular- and animal models with state-of-the-art neurobiological, molecular biological and immunobiological approaches.

小脑共济失调是一种进行性神经退行性疾病，严重影响患者的日常生活 人们，他们的家庭，以及医疗保健系统。小脑性共济失调是无法治愈的， 起源没有有效的治疗方法来减缓经常导致早产的症状的进展。 死亡离子通道与几种形式的小脑共济失调的病因有关。比如说， KCNC 3中的特定突变，编码Kv3.3通道的基因，如G592 R点突变， 被确定为晚发性脊髓小脑共济失调的潜在遗传原因。尽管有这些 尽管研究进展缓慢，但对于为什么迟发性小脑共济失调会出现在某些而非所有受试者中， 基因突变。在受影响受试者的生命周期中， 症状出现。基于我们意想不到的初步观察，我们假设疾病的发作是在 遗传易感受试者是由宿主-病原体相互作用决定的，特别强调病毒感染。 感染.具体地说，我们断言，协同激活的细胞内信号通路， 被突变钾通道和病毒防御机制靶向，损害细胞功能， 导致浦肯野细胞死亡。我们的假设和初步数据挑战了当代关于 小脑性共济失调的病因及其新的治疗策略我们将使用以下方法来检验我们的假设： 细胞和动物模型，具有最先进的神经生物学、分子生物学和免疫生物学 接近。

项目成果

Response to: Elevated L1 expression in ataxia telangiectasia likely explained by an RNA-seq batch effect.

反应：共济失调毛细血管扩张症中 L1 表达升高可能是通过 RNA-seq 批次效应来解释的。

• DOI: 10.1016/j.neuron.2023.02.006
• 发表时间: 2023
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Takahashi,Takehiro;Stoiljkovic,Milan;Song,Eric;Gao,Xiao-Bing;Yasumoto,Yuki;Kudo,Eriko;Carvalho,Fernando;Kong,Yong;Park,Annsea;Shanabrough,Marya;Szigeti-Buck,Klara;Liu,Zhong-Wu;Kristant,Ashley;Zhang,Yalan;Sulkowski,Parker;Glaz
• 通讯作者: Glaz