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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：
7246777
负责人：
BENOIT I GIASSON
金额：
$ 26.42万
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/7246777
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。分享了很多