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Targeting Tau Proteoforms in Frontotemporal Dementia

额颞叶痴呆中的靶向 Tau 蛋白变体

基本信息

批准号：
10306108
负责人：
Celeste Marie Karch
金额：
$ 181.5万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10306108
关键词：
Affect Alleles Alzheimer&apos s Disease Antisense Oligonucleotides Astrocytes Binding Biochemical Biological Process Brain Brain region CRISPR/Cas technology Cell Nucleus Cerebrospinal Fluid Characteristics Coculture Techniques Defect Disease Dominant Genes Enzymes Equilibrium Event Exhibits Frontotemporal Dementia Frontotemporal Lobar Degenerations Functional disorder Genes Genetic Goals Half-Life Haplotypes Human Impairment Induced pluripotent stem cell derived neurons Inherited Kinetics Lead Link Lysosomes MAPT gene Maps Messenger RNA Metabolism Methods Modification Molecular Molecular Profiling Monitor Mutagenesis Mutation Nerve Degeneration Neuronal Dysfunction Neurons Pathogenesis Pathologic Pathway interactions Phenotype Process Progressive Supranuclear Palsy Proteomics RNA Splicing Risk Stable Isotope Labeling Structure Tauopathies Technology Testing Therapeutic brain tissue cell type corticobasal degeneration design disorder risk extracellular induced pluripotent stem cell mRNA Precursor mutant novel novel therapeutic intervention proteostasis stem cells targeted treatment tau Proteins tau aggregation tau expression tau-1 therapeutic target transcriptome transcriptome sequencing transcriptomics

项目摘要

Tauopathies may occur by familial mechanisms in which mutations in the MAPT gene are dominantly inherited causing frontotemporal lobar degeneration (FTLD-tau) or by sporadic mechanisms in which MAPT haplotypes are associated with increased disease risk (e.g. progressive supranuclear palsy and corticobasal degeneration). MAPT mutations and risk haplotypes have been proposed to drive disease pathogenesis through proteoforms that contain 3-microtubue binding domain repeats (3R tau), 4R tau, or both. However, the mechanisms by which tauopathies occur remains poorly understood. We propose that MAPT mutations drive tau aggregation and neuronal dysfunction through altered proteostasis. In preliminary studies, we have shown that induced pluripotent stem cell derived-neurons expressing MAPT mutations exhibit changes in tau turnover compared to isogenic, control neurons, and we observed differences in the turnover of specific tau proteoforms in mutant neurons. Neurons expressing MAPT mutations exhibit enlarged lysosomal structures and secondary elevation of lysosomal enzymes, markers of lysosomes that are unable to properly degrade their contents. Correction of the mutant allele was sufficient to restore these lysosomal defects. This suggests that altered tau kinetics may be due to defects in the endolysosomal pathway. Thus, a unifying feature by which MAPT mutations drive tauopathy is through disrupted proteostasis. The objective of this study is to extend our preliminary findings to manipulate tau proteoforms using genetic or molecular methods to define the mechanisms by which tau proteoforms disrupt proteostasis in tauopathies. We hypothesize that tau proteoforms are sufficient to destabilize proteostasis and to result in the accumulation of tau in vulnerable brain regions. To test this hypothesis, we will determine the extent to which MAPT mutations cause impaired tau phenotypes and proteostasis characteristic of tauopathy. We will also generate a systematic genetic interaction map to elucidate connections between MAPT mutations, proteostasis, and associated therapeutic targets. Together, this study will reveal novel mechanisms underlying tauopathy that are driven by specific tau proteoforms and whether therapeutics designed to block specific tau proteoforms impact pathologic events.

肌萎缩侧索硬化症可能由家族性机制发生，其中MAPT基因突变占主导地位遗传性致额颞叶变性(FTLD-tau)或由MAPT 单倍型与疾病风险增加相关(例如进行性核上性麻痹和皮质基底细胞麻痹退化)。MAPT突变和风险单倍型已被认为是疾病发病的驱动因素通过含有3-微管结合结构域重复序列(3R Tau)、4R tau或两者的蛋白形式。然而，肌萎缩侧索硬化症的发生机制仍然知之甚少。我们认为MAPT突变驱动 Tau的聚集和通过蛋白平衡改变的神经元功能障碍。在初步研究中，我们已经表明诱导表达MAPT突变的多能干细胞来源的神经元表现出tau周转的变化与同基因的对照神经元相比，我们观察到特定tau蛋白形式的周转不同在突变的神经元中。表达MAPT突变的神经元表现为溶酶体结构扩大和继发性溶酶体酶升高，溶酶体标记物不能适当地降解其内容物。对突变等位基因的纠正足以修复这些溶酶体缺陷。这表明改变的tau蛋白动力学可能是由于内切酶途径的缺陷所致。因此，MAPT的一个统一特征是突变通过被破坏的蛋白平衡来驱动紧张症。这项研究的目的是扩大我们的使用基因或分子方法来确定tau蛋白形式的初步发现 Tau蛋白形式破坏tau病中的蛋白平衡的机制。我们假设Tau 蛋白形式足以破坏蛋白稳定，并导致tau在脆弱的大脑中积聚。地区。为了验证这一假设，我们将确定MAPT突变导致tau受损的程度肌萎缩侧索硬化症的表型和蛋白平衡特征。我们还将产生一种系统的遗传互动 MAP以阐明MAPT突变、蛋白平衡和相关治疗靶点之间的联系。总而言之，这项研究将揭示由特定tau驱动的tau病的新机制蛋白形式以及为阻断特定tau蛋白形式而设计的治疗方法是否会影响病理事件。