Identification of novel four repeat tauopathies through analysis of network vulnerability, tau structure and propagation.

通过分析网络脆弱性、tau 结构和传播来识别新型四种重复 tau 病。

• 批准号: 10562726
• 负责人: BERNARDINO Francesco GHETTI
• 金额: $ 68.63万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10562726
• 关键词: Address; Affect; Alzheimer' s Disease; Astrocytes; Behavioral; Biochemical; Biological Models; Brain; Brain region; Categories; Clinical; Coiled Bodies; Collection; Cryoelectron Microscopy; Custom; Deglutition Disorders; Diagnosis; Disease; Filament; Frontotemporal Dementia; Genetic; Goals; Guidelines; Hippocampus; Histologic; Human; Impaired cognition; In Vitro; Inclusion Bodies; Indiana; Individual; Investigation; Lead; Microfluidic Microchips; Modeling; Molecular; Molecular Conformation; Movement; Mus; Names; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Neuropil Threads; Pathologic; Pathology; Pathway Analysis; Patients; Pattern; Pick Disease of the Brain; Polymorph; Post-Translational Protein Processing; Prevalence; Progressive Supranuclear Palsy; Resolution; Specificity; Structure; Symptoms; Tauopathies; Therapeutic Studies; Time; Validation; Variant; Work; behavioral impairment; clinical diagnosis; clinical subtypes; cohort; conformer; corticobasal degeneration; design; diagnostic criteria; frontal lobe; gaze; gaze palsy; genetic analysis; immunoreactivity; improved; in vivo; in vivo Model; mouse model; multidisciplinary; neurodegenerative dementia; neuropathology; new technology; novel; novel diagnostics; novel therapeutics; posture instability; tau Proteins; tau aggregation; technology platform

Recently, significant progress in understanding tauopathies and how tau aggregates lead to neurodegeneration has been made by the description of the atomic structures of tau filaments from human brain. We have determined structures (resolutions of up to 2.7Å) of tau filaments from three individuals with typical progressive supranuclear palsy (PSP) and four with variant PSP. Clinically, typical cases of PSP are characterized by postural instability, supranuclear gaze palsy, behavioral and cognitive impairment, as well as bulbar symptoms. Neuropathologically, they are defined by abundant subcortical neurofibrillary tangles and neuropil threads (composed of 4R tau), together with tufted astrocytes and oligodendroglial coiled bodies. Atypical forms of PSP may be distinguished by differences in tau load in specific brain regions. In all cases of PSP, tau filaments are made of a single protofilament with an ordered core (PSP fold). During our study, we identified one case that had a different tau structure. Histologically, this case was also different from PSP because displayed abundant spherical, 4R tau immunoreactive, basophilic neuronal inclusions in frontal cortex and limbic structures. We named this disease ‘limbic-predominant neuronal inclusion body 4R tauopathy’ (LNT). LNT is a novel form of 4R tauopathy. The studies proposed in this MPI application are a logical continuation of this groundbreaking work. Cryo-EM analysis of an additional “PSP” case showed a different fold and histological profile from PSP (LNT-II). The overall goal of this application is to determine the prevalence of LNT in two large cohorts of PSP cases (Indiana and Toronto cohorts), characterize LNT-I and –II, two novel 4R tauopathies, and determine whether additional novel 4R entities can be identified that were previously diagnosed as PSP. We will also provide biochemical and structural validation of in vitro and in vivo models for mechanistic and therapeutic studies. In order to achieve our goals, our proposal has three specific aims. The first is to perform neuropathologic, genetic, and cryo-EM studies on a large cohort of PSP cases to characterize the prevalence and neuropathologic features of LNT and assess whether additional entities are present (and their tau structure). Second, we will identify the molecular changes occurring in tau in LNT-I/–II and characterize the seeding ability and potency of tau in vitro. Lastly, we will characterize the propagation of tau filaments from PSP and LNT-I/-II patients using custom microfluidic devices and a murine model. We will determine the atomic structure of seeded filaments from mice and assess whether tau conformers and their structural polymorphs are propagated true to their original form in vivo.

最近，通过描述人脑中tau蛋白丝的原子结构，在理解tau蛋白病以及tau蛋白聚集体如何导致神经变性方面取得了重大进展。我们已经确定了结构（分辨率高达2.7 μ m）的tau纤维从三个典型的进行性核上性麻痹（PSP）和四个变异PSP的个人。临床上，PSP的典型病例以姿势不稳、核上性凝视麻痹、行为和认知障碍以及延髓症状为特征。在神经病理学上，它们由丰富的皮质下神经纤维缠结和神经纤维丝（由4 R tau组成）以及簇状星形胶质细胞和少突胶质细胞卷曲体定义。PSP的非典型形式可以通过特定脑区域中tau负载的差异来区分。在PSP的所有情况下，tau丝由具有有序核心（PSP折叠）的单个原丝组成。在我们的研究中，我们发现了一个具有不同tau结构的病例。在组织学上，该病例也不同于PSP，因为在额叶皮质和边缘结构中显示丰富的球形、4 R tau免疫反应阳性、嗜碱性神经元包涵体。我们将这种疾病命名为“边缘主导的神经元包涵体4 R tau蛋白病”（LNT）。LNT是4 R tau蛋白病的一种新形式。在这个MPI应用程序中提出的研究是这一开创性工作的逻辑延续。另一例“PSP”病例的冷冻EM分析显示与PSP（LNT-II）不同的折叠和组织学特征。本申请的总体目标是确定LNT在两个大型PSP病例队列（印第安纳州和多伦多队列）中的患病率，表征LNT-I和-II（两种新型4 R tau蛋白病），并确定是否可以鉴定出先前诊断为PSP的其他新型4 R实体。我们还将为机制和治疗研究提供体外和体内模型的生物化学和结构验证。为了实现我们的目标，我们的建议有三个具体目标。第一个是对大量PSP病例进行神经病理学、遗传学和冷冻电镜研究，以表征LNT的患病率和神经病理学特征，并评估是否存在其他实体（及其tau结构）。第二，我们将鉴定LNT-I/-II中tau中发生的分子变化，并表征tau的体外接种能力和效力。最后，我们将使用定制的微流体装置和鼠模型表征来自PSP和LNT-I/-II患者的tau细丝的传播。我们将确定来自小鼠的种子丝的原子结构，并评估tau构象异构体及其结构多晶型物是否在体内以其原始形式繁殖。