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Misfolding and aggregation of polyglutamine sequences in neurodegenerative diseases

神经退行性疾病中多聚谷氨酰胺序列的错误折叠和聚集

基本信息

批准号：
9036812
负责人：
Samuel A Kotler
金额：
--
依托单位：
U.S. NATIONAL INST DIABETES/DIGST/KIDNEY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-10-01 至 2018-10-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9036812
关键词：
Adenine Affect Alzheimer&apos s Disease Amino Acid Sequence Amyloid Amyloidosis Animals Biochemical Calorimetry Cell Nucleus Cell physiology Characteristics Clinical Contracts Cytosine Data Development Disease Disease Progression Electron Spin Resonance Spectroscopy Exons Fluorescence Spectroscopy Genes Goals Guanine Homeostasis Huntington Disease Huntington gene Investigation Kinetics Knowledge Lead Length Localized Disease Mediating Methodology Methods Molecular Molecular Chaperones Mutate Mutation N-terminal NMR Spectroscopy Nature Nerve Degeneration Neurodegenerative Disorders Neuronal Dysfunction Non-Insulin-Dependent Diabetes Mellitus Nuclear Magnetic Resonance Onset of illness Outcome Parkinson Disease Pathogenesis Peptide Fragments Peptides Play Process Property Protein Fragment Proteins Proteolysis Published Comment Quality Control Resistance Resolution Role Structure Syndrome System Therapeutic Tissues Toxic effect Trinucleotide Repeat Expansion Work amyloid formation beta pleated sheet biophysical techniques conformer insight interest mitochondrial dysfunction mutant nervous system disorder neurotoxicity neutrophil overexpression polyglutamine protein aggregate protein folding protein misfolding public health relevance self assembly therapeutic development

项目摘要

DESCRIPTION (provided by applicant): The formation of accumulated, abnormally folded proteins is associated with more than twenty different clinical syndromes, each of which is associated with a distinct `misfolding' protein. These misfolded proteins aggregate and form the hallmarks of many neurodegenerative diseases, termed amyloids. Amyloid formation is associated with neurodegenerative disseases such as Alzheimer's, Parkinson's, and Huntington's disease, as well as localized diseases such as Type II Diabetes. Of the amyloid-related diseases, polyglutamine (polyQ) diseases represent a set of heritable neurological disorders, comprising at least nine diseases. In polyQ diseases like Huntington's disease (HD), our knowledge of how and why an expanded tract of polyQ leads to aggregation and amyloid formation is largely hampered by the fact that there is little high-resolution structural and dynamic insight into this process. Furthermore, the ability of a polyQ protein misfolded species to engage in aberrant protein interactions has become increasingly studied. Particularly, the interactions of polyQ proteins with molecular chaperones and their resistance to proteolysis are poorly understood. Challenges posed by polyQ proteins are manifold and, therefore, new biochemical and biophysical approaches developed to tackle such problems would greatly aid our understanding of polyQ diseases. To accomplish this goal, this application seeks to further investigate the aggregative properties of polyQ proteins at high-resolution, namely the N- terminal fragment of the huntingtin protein (implicated in the progression of HD), by using by nuclear magnetic resonance (NMR) spectroscopy. Newly developed NMR methods, such as dark-state exchange saturation transfer (DEST) and lifetime line broadening, offer the capability to achieve atomic resolution on the dynamic exchange occurring in the self-assembly of polyQ proteins, in addition to their interactions with molecular chaperones such as Hsp70 and Hsp40. While this proposal will focus on the development and application of new NMR methodologies to such challenging systems, the study will be extended for investigation using a variety of other biophysical techniques, including electron paramagnetic resonance (EPR), fluorescence spectroscopy, and calorimetry. The outcome of the proposed studies on amyloid formation by polyQ proteins will significantly advance our understanding of HD and other polyQ diseases, in general, by achieving structural and dynamic insights with atomic-level resolution and will aid in the development of therapeutic strategies for such diseases.