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，通过对人脑tau蛋白细丝原子结构的描述，在理解tau病变和tau蛋白聚集体如何导致神经退行性变方面取得了重大进展。我们已经确定了三名典型进行性核上性麻痹（PSP）患者和四名变异型PSP患者的tau蛋白丝的结构（分辨率高达2.7Å）。临床上，典型的PSP病例表现为体位不稳、核上凝视性麻痹、行为和认知障碍以及球症状。在神经病理学上，它们被定义为丰富的皮层下神经原纤维缠结和神经丝（由4R tau组成），以及簇状星形胶质细胞和少突胶质卷曲体。非典型形式的PSP可以通过特定脑区tau负荷的差异来区分。在PSP的所有情况下，tau细丝都是由具有有序核心（PSP折叠）的单个原细丝组成的。在我们的研究中，我们发现了一个具有不同tau结构的病例。组织学上，该病例也与PSP不同，在额叶皮层和边缘结构中表现出丰富的球形、4R tau免疫反应性、嗜碱性神经元包涵体。我们将这种疾病命名为“边缘主导型神经元包涵体4R tau病”（LNT）。LNT是一种新型的4R牛头病。在这个MPI应用中提出的研究是这个开创性工作的逻辑延续。另一个“PSP”病例的冷冻电镜分析显示了与PSP （LNT-II）不同的折叠和组织学特征。本应用程序的总体目标是确定两大PSP病例队列（印第安纳州和多伦多队列）中LNT的患病率，表征LNT- i和LNT -II这两种新型4R病变，并确定是否可以识别先前诊断为PSP的其他新型4R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化和结构验证。为了实现我们的目标，我们的提案有三个具体目标。首先是对大量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）。其次，我们将确定LNT-I/ -II中tau发生的分子变化，并表征tau在体外的播种能力和效力。最后，我们将使用定制的微流体装置和小鼠模型来表征PSP和LNT-I/-II患者tau蛋白细丝的繁殖。我们将确定小鼠种子细丝的原子结构，并评估tau构象及其结构多态性是否在体内真实地传播到其原始形式。