Interactions of Protein Aggregation in Parkinson's Dementia

帕金森痴呆症中蛋白质聚集的相互作用

基本信息

批准号：
7643105
负责人：
BENOIT I GIASSON
金额：
$ 27.35万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7643105
关键词：
Address Alzheimer&apos s Disease Amino Acids Amyloid Amyloid beta-Protein Behavioral Biological Brain Cells Cessation of life Characteristics Clinical Dementia Deposition Disease Event Functional disorder Goals Impairment In Vitro Inherited Knowledge Lead Lesion Lewy Bodies Lewy Body Disease Mediating Midbrain structure Missense Mutation Modification Molecular Motor Movement Disorders Mutation Nerve Degeneration Neurites Neurodegenerative Disorders Neuronal Dysfunction Neurons Numbers Pan Genus Parkinson Disease Parkinson&apos s Dementia Pathogenesis Pathology Patients Peptides Physiological Process Property Proteins Rate SNCA gene Testing Therapeutic Transgenic Mice Transgenic Organisms Translations Tube Variant alpha synuclein base disease characteristic dopaminergic neuron extracellular in vivo insight kindred mouse model polymerization protein aggregation research study synuclein tau Proteins tau aggregation tau interaction

项目摘要

Parkinson's disease (PD), is the most common neurodegenerative movement disorder, and it^.shares many common features, such as protein aggregation, with a broader spectrum of neutodegenerative diseases. PD can present with additional clinical impairments and dementia is common in PD patients. Despite the knowledge that the loss of specific dopaminergic neurons in the midbrain is largely responsible for most of the motor dysfunction in PD, there are significant unknown about the mechanism that lead to neuronal death. Although familial PD is relatively rate, the identification of mutation in the alpha-synuclein gene has lead to the discovery that this protein is the major component of disease-characteristic inclusions known as Lewy bodies and Lewy neurites. Alpha-synuclein is normally a soluble protein, but it can polymerize into 10-15 nm fibrils with specific biophysical properties known as "amyloid" to form pathological inclusions. Pathological inclusions such as intracellular neurofibrillarytangles and extracellular Abeta peptide deposits, which are characteristic of Alzheimer's diseasae, frequently present concomitantly with alpha-synyuclein aggregates. Indeed, apha-synuclein and tau inclusions can occur in the same cells, often intertwined. Alpha-synuclein has been shown to be able to act as an induceer of tau aggregation, and both proteins can enhance the ploymerization of each other once this process is initiated. However, the molecular mechanism and the physiological changes that lead to this process have not been elucidated. Test tube experiments and transgenic mice studies will be conducted to address these issues. Studies will be conducted to assess selective vulnerability and behavioral impairments in transgenic mice resulting from alpha-synuclein and tau interactions leading to the formation of pathological consequences. Aberrant physiological alterations,such as nitrative damage and hyperphosphorylation, may be involved in mediating alpha-synuclein and tau interactions and these mechanisms will be investigated. Transgenic mouse models of Abeta peptide deposits will also be used to assess possible pathological mechanisms by which these inclusions may promote alpha-synuclein aggregation. These findings shown provide important information on mechanisms and physiological changes that lead to the formaion of alpha-synuclein and tau inclusions, and may lead to insights in planning for effective therapeutic approaches.

帕金森病 (PD) 是最常见的神经退行性运动障碍，它^.有许多共同点蛋白质聚集等共同特征与更广泛的神经退行性疾病有关。 PD 可能会出现额外的临床损伤，痴呆症在帕金森病患者中很常见。尽管了解中脑中特定多巴胺能神经元的丧失在很大程度上是造成大多数 PD 运动功能障碍导致神经元死亡的机制尚不清楚。尽管家族性帕金森病发生率相对较高，但α-突触核蛋白基因突变的发现已导致发现这种蛋白质是被称为路易 (Lewy) 的疾病特征内含物的主要成分体和路易神经突。 α-突触核蛋白通常是可溶性蛋白质，但它可以聚合成 10-15 nm 具有称为“淀粉样蛋白”的特定生物物理特性的原纤维形成病理包涵体。病理性的细胞内神经原纤维缠结和细胞外 Abeta 肽沉积物等内含物阿尔茨海默氏病的特征，经常与 α-突触核蛋白聚集物同时存在。事实上，apha-突触核蛋白和 tau 蛋白包涵体可以出现在同一细胞中，并且通常交织在一起。 α-突触核蛋白已被证明能够充当 tau 聚集的诱导剂，并且这两种蛋白质都可以增强一旦该过程开始，就会相互聚合。然而，分子机制和导致这一过程的生理变化尚未阐明。试管实验和将进行转基因小鼠研究来解决这些问题。将进行研究以评估 α-突触核蛋白和 tau 蛋白导致转基因小鼠的选择性脆弱性和行为障碍相互作用导致形成病理后果。异常的生理变化，例如作为硝基损伤和过度磷酸化，可能参与介导 α-突触核蛋白和 tau 蛋白相互作用和这些机制将被研究。 Abeta肽转基因小鼠模型沉积物还将用于评估这些夹杂物可能的病理机制促进α-突触核蛋白聚集。这些发现提供了有关机制的重要信息和导致 α-突触核蛋白和 tau 包含物形成的生理变化，并可能导致规划有效治疗方法的见解。