Elucidating The Aberrant TDP-43 Species That Promote Neurodegeneration

阐明促进神经退行性变的异常 TDP-43 物种

• 批准号: 10385722
• 负责人: Todd Jonathan Cohen
• 金额: $ 34.02万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10385722
• 关键词: ALS patients; Acetylation; Alzheimer' s Disease; Automobile Driving; Behavior; Behavioral; Biochemical; Cell Nucleus; Cessation of life; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Cognition Disorders; Cognitive deficits; Data; Defect; Detection; Disease; Disease Progression; Dissociation; Event; Functional disorder; Future; Gene Expression Profile; Genetic Transcription; Goals; HSF1; Histology; Human; Impairment; Individual; Knock-in Mouse; Light; Link; Lysine; Messenger RNA; Modeling; Modification; Molecular Chaperones; Motor Neurons; Mus; Mutant Strains Mice; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Neurons; Nuclear; Onset of illness; Pathogenesis; Pathogenicity; Pathologic; Pathology; Physiological; RNA Recognition Motif; Role; Signal Transduction; Symptoms; Syndrome; Testing; Therapeutic; Toxic effect; approach behavior; base; effective therapy; frontotemporal lobar dementia-amyotrophic lateral sclerosis; gain of function; human disease; in vivo; in vivo evaluation; innovation; insight; motor deficit; motor disorder; mouse model; neurodegenerative phenotype; neuron loss; prevent; protein TDP-43; proteostasis; response; therapeutic target; transcription factor; transcriptome; transcriptome sequencing; treatment strategy

TDP-43 dysfunction underlies a spectrum of neurodegenerative diseases collectively known as TDP-43 proteinopathies, which are characterized by neuronal loss, behavioral abnormalities, and ultimately death. Surprisingly, little is known about how TDP-43 undergoes such a dramatic transformation that initiates disease progression. Recently, we discovered that TDP-43 is subject to reversible lysine acetylation, a modification within TDP-43’s RNA-binding domain that has a remarkable effect; it disengages TDP-43 from its target mRNAs and accelerates TDP-43’s propensity to aggregate. Indeed, acetylated TDP-43 inclusions were detected in motor neurons of amyotrophic lateral sclerosis (ALS) patients, suggesting a role for this aberrantly modified form of TDP-43 in disease pathogenesis. We leveraged this intriguing finding to generate the first CRISPR-based, non-transgenic TDP-43 mouse model containing an acetylation-mimicking mutation, thus producing a physiologically relevant model of TDP-43 proteinopathy. We hypothesize that TDP-43 acetylation drives neurodegeneration and disease progression, which can now be directly tested in vivo. Our preliminary data already show evidence of TDP-43 pathology, nuclear TDP-43 clearing, and prominent behavioral defects in mutant mice. In Aim-1, we will use histology, biochemical, and behavior approaches to fully characterize the neurodegenerative phenotype. In Aim-2, we shed light on the therapeutic potential of activating the master transcription factor HSF1, or specific downstream chaperones, to induce a highly coordinated transcriptional cascade capable of suppressing acetylated TDP-43 dysfunction and restoring nuclear TDP-43 levels. Finally, in Aim-3, we will uncover early-stage perturbations in the transcriptome that occur in response to acetylated TDP-43, but emerge prior to overt neurodegeneration and behavioral defects. Our proposal is significant since it will highlight an aberrant form of TDP-43 as a plausible therapeutic target, it will pinpoint specific chaperone responses as new avenues to detoxify neurons, and it will illuminate transcriptional dysregulation as a critical pathomechanism associated with neurodegeneration. Our proposal is also innovative since we will shed light on aberrant TDP-43 modifications as plausible triggers for disease onset or progression.

TDP-43 功能障碍是统称为 TDP-43 的一系列神经退行性疾病的基础 蛋白质病，其特征是神经元丢失、行为异常，并最终死亡。 令人惊讶的是，人们对 TDP-43 如何经历如此巨大的转变并引发疾病知之甚少 最近，我们发现 TDP-43 发生可逆赖氨酸乙酰化，这是一种修饰 在 TDP-43 的 RNA 结合域内，具有显着的作用，可以使 TDP-43 脱离其靶标； 事实上，乙酰化的 TDP-43 内含物会加速 TDP-43 的聚集。 在肌萎缩侧索硬化症 (ALS) 患者的运动神经元中检测到，表明这种作用异常 我们利用这一有趣的发现产生了第一个疾病发病机制中的 TDP-43 修饰形式。 基于 CRISPR 的非转基因 TDP-43 小鼠模型含有乙酰化模拟突变，因此 产生 TDP-43 蛋白病的生理相关模型。 乙酰化会导致神经变性和疾病进展，现在可以直接在 我们的初步数据已经显示了 TDP-43 病理学、核 TDP-43 清除和的证据。 在 Aim-1 中，我们将使用组织学、生物化学和行为来观察突变小鼠的显着行为缺陷。 在 Aim-2 中，我们阐明了治疗方法。 激活主转录因子 HSF1 或特定下游伴侣的潜力，以诱导 高度协调的转录级联能够抑制乙酰化 TDP-43 功能障碍 最后，在 Aim-3 中，我们将发现核 TDP-43 的早期扰动。 转录组响应乙酰化 TDP-43 而发生，但在明显的神经变性之前出现 我们的提议很重要，因为它将突出 TDP-43 的异常形式作为一种合理的形式。 治疗目标，它将确定特定的伴侣反应作为解毒神经元的新途径，并且它将 阐明转录失调是与神经变性相关的关键病理机制。 该提案也是创新的，因为我们将阐明异常的 TDP-43 修改作为合理的触发因素 疾病发作或进展。

项目成果

Tandem detergent-extraction and immunoprecipitation of proteinopathy: Scalable enrichment of ALS-associated TDP-43 aggregates.

蛋白病的串联去垢剂萃取和免疫沉淀：ALS 相关 TDP-43 聚集体的可扩展富集。

• 发表时间: 2023-05-19
• 影响因子: 5.8
• 作者: Evangelista, Baggio A;Cahalan, Shannon R;Ragusa, Joey V;Mordant, Angie;Necarsulmer, Julie C;Perna, Robert J;Ajit, Tejazaditya;White, Kristen;Barker, Natalie K;Tian, Xu;Cohen, Sarah;Meeker, Rick;Herring, Laura E;Cohen, Todd J
• 通讯作者: Cohen, Todd J

Identification of distinct N-glycosylation patterns on extracellular vesicles from small-cell and non-small-cell lung cancer cells.

鉴定小细胞和非小细胞肺癌细胞的细胞外囊泡上不同的 N-糖基化模式。

• 发表时间: 2022-06
• 作者: Kondo, Kiyotaka;Harada, Yoichiro;Nakano, Miyako;Suzuki, Takehiro;Fukushige, Tomoko;Hanzawa, Ken;Yagi, Hirokazu;Takagi, Koichi;Mizuno, Keiko;Miyamoto, Yasuhide;Taniguchi, Naoyuki;Kato, Koichi;Kanekura, Takuro;Dohmae, Naoshi;Machida, Kentaro
• 通讯作者: Machida, Kentaro