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

• 批准号: 8298525
• 负责人: BENOIT I GIASSON
• 金额: $ 26.76万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8298525
• 关键词: Address; Alzheimer' s Disease; Amino Acids; Amyloid; Amyloid beta-Protein; 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; Parkinson Disease; Parkinson' s Dementia; Pathogenesis; Pathology; Patients; Peptides; Physiological; Process; Property; Proteins; SNCA gene; Testing; Therapeutic; Transgenic Mice; Translations; Tube; Variant; alpha synuclein; alpha synuclein gene; base; behavioral impairment; disease characteristic; dopaminergic neuron; extracellular; in vivo; insight; kindred; mouse model; polymerization; protein aggregation; research study; synuclein; tau Proteins; tau aggregation; tau interaction

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，它有许多共同之处 常见的特征，如蛋白质聚集，与更广泛的神经退行性疾病的范围。PD 可出现额外的临床损害，痴呆症在帕金森病患者中很常见。尽管 了解到中脑中特定多巴胺能神经元的丧失是导致大多数 帕金森病患者的运动功能障碍，其导致神经元死亡的机制尚不清楚。 尽管家族性帕金森病的发病率相对较高，但α-突触核蛋白基因突变的鉴定导致了 发现这种蛋白质是被称为路易氏的疾病特征包涵体的主要成分 身体和路易神经突起。α-突触核蛋白通常是一种可溶性蛋白质，但它可以聚合成10-15 nm 具有特定生物物理特性的纤维，称为“淀粉样蛋白”，形成病理性包裹体。病理性的 内含物，如细胞内神经原纤维缠结和细胞外Abeta肽沉积，它们是 阿尔茨海默病的特征，常与α-突触核蛋白聚集体同时出现。 事实上，APHA-突触核蛋白和tau包涵体可以出现在相同的细胞中，通常是相互缠绕的。α-突触核蛋白 已被证明能够作为tau聚集的诱导剂，这两种蛋白质都可以增强 一旦这一过程开始，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，以解决这些问题。将进行研究以评估 α-突触核蛋白和tau对转基因小鼠的选择性易感性和行为损伤 相互作用导致病理后果的形成。异常的生理变化，如 作为硝化损伤和过度磷酸化，可能参与介导α-突触核蛋白和tau 将对相互作用和这些机制进行研究。Abeta多肽转基因小鼠模型的建立 沉积物也将被用来评估这些包裹体可能的病理机制 促进α-突触核蛋白聚集。这些发现提供了有关机理的重要信息 以及导致α-突触核蛋白和tau包裹体形成的生理变化，并可能导致 在规划有效治疗方法方面的见解。