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.

帕金森氏病（PD），是最常见的神经退行性运动障碍，它^Share许多常见特征，例如蛋白质聚集，具有更广泛的中性疾病。 PD PD患者可能会出现其他临床障碍，而痴呆症很常见。尽管有知道中脑中特定多巴胺能神经元的丧失对大多数 PD中的运动功能障碍，导致神经元死亡的机制有很大的了解。尽管家族性PD是相对较高的速率，但α-突触核蛋白基因中突变的鉴定已导致发现该蛋白是疾病特征夹杂物的主要组成部分，称为Lewy 身体和路易神经突。 α-突触核蛋白通常是可溶性蛋白，但可以分成10-15 nm 具有特定生物物理特性的原纤维被称为“淀粉样蛋白”以形成病理夹杂物。病理包括细胞内神经原纤维中的夹杂物和细胞外abeta肽沉积物，它们是阿尔茨海默氏症疾病的特征，经常与alpha-synyuclein骨料同时发生。实际上，Apha-核蛋白和Tau夹杂物可能发生在相同的细胞中，通常交织在一起。 α-核蛋白已被证明能够充当tau聚集的诱导者，两种蛋白质都可以增强启动此过程后，彼此之间的绘画化。但是，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以解决这些问题。将进行研究以评估 α-核蛋白和tau引起的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。异常的生理改变作为硝酸损伤和高磷酸化，可能参与介导α-核蛋白和tau 相互作用和这些机制将进行研究。 Abeta肽的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-核蛋白聚集。所示的这些发现提供了有关机制的重要信息以及导致α-突触核蛋白和tau夹杂物的甲型的生理变化，并可能导致计划有效治疗方法的见解。