Novel misfolded proteins in ADRD: proteomics, genetics, and clinical-pathological correlations

ADRD 中的新型错误折叠蛋白：蛋白质组学、遗传学和临床病理相关性

• 批准号: 9905466
• 负责人: PETER T. NELSON
• 金额: $ 19.13万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9905466
• 关键词: Age; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Amygdaloid structure; Amyloid beta-Protein; Animal Model; Automobile Driving; Autopsy; Biochemical; Biochemistry; Biological Markers; Brain; Brain Diseases; Candidate Disease Gene; Cessation of life; Chromosome Mapping; Clinical; Clinical Data; Core Facility; Correlation Studies; Data; Databases; Dementia; Detergents; Development; Diagnostic; Disease; Education; Elderly; Electrospray Ionization; Freezing; Funding Mechanisms; Future; Genes; Genetic; Genetic study; Genie; Genomics; Goals; Hand; Heterogeneity; Human; Image; Immunohistochemistry; Impaired cognition; Impairment; Individual; Kentucky; Knowledge; Liquid Chromatography; Mass Spectrum Analysis; Mutation; Neurodegenerative Disorders; Neurofibrillary Tangles; Pathogenicity; Pathologic; Pathology; Persons; Process; Proteins; Proteome; Proteomics; Public Health; Reporting; Research; Research Project Grants; Sampling; Seasons; Series; Severities; Statistical Data Interpretation; Statistical Models; TDP-43 aggregation; Testing; Therapeutic; Universities; University resources; Urea; Work; aged; aging brain; alpha synuclein; base; biobank; cerebrovascular pathology; clinical Diagnosis; cohort; demented; endophenotype; frontotemporal lobar dementia-amyotrophic lateral sclerosis; genetic risk factor; genetic variant; insight; large scale data; misfolded protein; multidisciplinary; neuropathology; novel; polypeptide; protein TDP-43; protein misfolding; sex; synuclein; tandem mass spectrometry; tau Proteins

The heterogeneous pathologies of Alzheimer's disease and related dementias (ADRD) are still incompletely understood. There is no perfect animal model to study these diseases. Four known aberrantly misfolded proteins are commonly detected via neuropathologic examination of brains with ADRD: Aβ, Tau, TDP-43, and/or α-Synuclein. Our preliminary data indicate that there are more pathogenic protein species awaiting identification. Characterization of these proteins may be relevant to the development of both diagnostic and therapeutic strategies for ADRD. The goals of this research project are to identify previously uncharacterized, misfolded, and aberrantly processed proteins in ADRD; to resolve gene variants that modulate the severity and heterogeneity of dementia through the novel misfolded proteins; and, to perform clinical-pathological correlation, focusing on these novel proteins, to identify new disease-associated pathologic biomarkers. We will leverage the resources of the University of Kentucky AD Center (UK-ADC) biobank and the University of Kentucky Proteomics Core Facility, to execute the following Specific Aims: Specific Aim 1. Analyse detergent-insoluble protein extracts from human amygdala (snap-frozen at autopsy) to investigate whether as yet uncharacterized misfolded proteins are detectable in ADRD. Polypeptides from the detergent-insoluble, urea-soluble protein fractions of amygdala will be interrogated using mass spectrometry. We have on-hand amygdalae from 40 UK-ADC subjects which incorporate a spectrum of clinical and pathologic features. Immunohistochemistry and biochemical studies will be performed to determine the best candidate proteins for additional studies (Aims 2 and 3). Specific Aim 2. Construct a robust and harmonized database with exonic sequencing to localize genetic regions associated with novel misfolded proteins in ADRD. We will test the association between dementia and rare, exonic (`mis-sense') genetic variants in genes that encode candidate misfolded proteins (Aim 1). Genetics data augmented with rich neuropathologic endophenotypes and longitudinal clinical data will enable insights into novel mechanisms that drive dementia. Large-scale datasets (NACC, ADGC, ADSP) will be aggregated and harmonized to test the genetic drivers of clinical and neuropathology-based endophenotypes focusing on novel candidate genes. Candidate target genes have already been identified. Specific Aim 3. Establish the clinical-pathologic correlation for the novel misfolded proteinopathies in ADRD. We will test the association between the potential novel proteinopathies (from Aim 1) with cognitive impairment, factoring in known markers Aβ, tau, α-Synuclein, and TDP-43, as well as cerebrovascular pathologies. We have 370 samples available for analyses (both sexes) from the UK-ADC, which should be statistically powered to test our hypothesis that the presence and severity of novel misfolding protein pathologies are associated with cognitive impairment.

阿尔茨海默病和相关痴呆（ADRD）的异质性病理仍然存在