Functional assessment of pathological α-syn and Aβ species in LBD
LBD 中病理 α-syn 和 Aβ 物种的功能评估
基本信息
- 批准号:10686906
- 负责人:
- 金额:$ 57.57万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-20 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:AllelesAlzheimer&aposs DiseaseAmyloid beta-ProteinAutophagocytosisAutopsyBiochemicalBiologicalBiological AssayBrainBrain regionCell modelCellsCharacteristicsClinicalCognitive deficitsCollaborationsComplementComplexDementiaDementia with Lewy BodiesDevelopmentDiagnosticDiseaseEndosomesEnzymesGeneticGenetic RiskGenetic VariationHealthHumanImmunoassayImpairmentIndividualInduced pluripotent stem cell derived neuronsKnowledgeLewy BodiesLewy Body DementiaLipidsLysosomesMeasuresMembraneMethodsMolecular ConformationMutationNeuronsParkinson DiseaseParkinson&aposs DementiaPathologicPathway interactionsPatientsPositioning AttributeProcessProteinsProteomicsReporterResearch PersonnelScanningSenile PlaquesSlideStructureSubcellular FractionsSystemTissuesToxic effectValidationabeta accumulationalpha synucleinarmbeta pleated sheetbrain tissuedementia riskgenetic risk factorglucosylceramidasein vivolipidomicsmotor deficitmotor symptomneuropathologyneurotoxicnovelphosphoneuroprotein 14prion-likeprotein structureresponsesingle moleculestructural determinantssuperresolution microscopysynergismtranscriptomics
项目摘要
ABSTRACT
Elucidation of underlying disease mechanisms in Lewy body dementia requires the systematic characterization
of disease-specific changes in LBD brain tissue. The combination of dementia and motor symptoms at the
clinical level is reflected in the neuropathology by the accumulation of alpha-synuclein (α-syn) in Lewy bodies
and beta-amyloid (Aβ) in amyloid plaques. Both Aβ and α-syn are capable of aggregating into oligomers, fibrils,
and beta sheets, but the aggregates that form are extremely heterogeneous in terms of both structure and
function. The identification of which specific subspecies of the proteins are neurotoxic or support aggregation is
poorly understood and as a result development of diagnostics and treatments that depend on knowledge of
protein structure has been slow. Recent studies have suggested a ”seeded” or “prion-like” propagation for both
α-syn and Aβ, indicating that abnormal conformations may ‘spread’ from diseased to healthy cells. While
synthetic seeds of α-syn and Aβ confer toxicity in cells through various mechanisms, it is well known that the
exact method of preparing these species influences their bioactivity to a high degree. Herein we take the next
important step to analyze the actual subspecies from post-mortem brains, to define and compare aggregates,
and identify mechanisms of toxicity and spreading underlying the selective regional vulnerabilities. We will
extract soluble and insoluble α-syn and Aβ species from neuropathologically confirmed LBD brains with or
without genetic LBD risk factors for structural and functional characterization. We will assess load and
distribution of α-syn and Aβ subspecies and will detail their characteristics including size, structure and self-
templating capabilities (Aim 1). The critical involvement of autophagy-lysosomal pathways in LBD is
emphasized by the underlying genetic risks for LBD. Besides mutations in glucocerebrosidase (GBA) that
interfere with lysosomal functions, it is well established that individuals with the APOE ϵ4 allele have a 6-fold
greater risk for DLB. We will assess alterations in lysosome function in LBD brain and determine their response
and contribution to processing, aggregation, and toxicity of α-syn and Aβ subspecies (Aim 2). We will use
patients’ iPSC-derived neurons with different genetic risk factors to functionally validate the contribution to
aggregation, toxicity and spreading of α-syn and Aβ (Aim 3). The expertise of this group of investigators
synergizes to identify differences in structure and function of subspecies, to investigate mechanisms of
aggregation and toxicity, and to unravel the contributions of the genetic variations and alterations in selective
autophagy pathways to regional vulnerabilities. This puts us in a unique position to complement the studies of
Projects 1, 2, and 3 of this CWOW at multiple levels and towards the full characterization of α-syn and Aβ
subspecies.
摘要
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Pamela J McLean其他文献
Pamela J McLean的其他文献
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{{ truncateString('Pamela J McLean', 18)}}的其他基金
Mitochondrial Sirtuin 3 in Parkinson's disease
线粒体 Sirtuin 3 在帕金森病中的作用
- 批准号:
10409706 - 财政年份:2019
- 资助金额:
$ 57.57万 - 项目类别:
Functional assessment of pathological α-syn and Aβ species in LBD
LBD 中病理 α-syn 和 Aβ 物种的功能评估
- 批准号:
10237303 - 财政年份:2019
- 资助金额:
$ 57.57万 - 项目类别:
Mitochondrial Sirtuin 3 in Parkinson's disease
线粒体 Sirtuin 3 在帕金森病中的作用
- 批准号:
10686813 - 财政年份:2019
- 资助金额:
$ 57.57万 - 项目类别:
Mitochondrial Sirtuin 3 in Parkinson's disease
线粒体 Sirtuin 3 在帕金森病中的作用
- 批准号:
10348483 - 财政年份:2019
- 资助金额:
$ 57.57万 - 项目类别:
Functional assessment of pathological α-syn and Aβ species in LBD
LBD 中病理 α-syn 和 Aβ 物种的功能评估
- 批准号:
10022185 - 财政年份:2019
- 资助金额:
$ 57.57万 - 项目类别:
Functional assessment of pathological α-syn and Aβ species in LBD
LBD 中病理 α-syn 和 Aβ 物种的功能评估
- 批准号:
10478195 - 财政年份:2019
- 资助金额:
$ 57.57万 - 项目类别:
Mitochondrial Sirtuin 3 in Parkinson's disease
线粒体 Sirtuin 3 在帕金森病中的作用
- 批准号:
9753438 - 财政年份:2019
- 资助金额:
$ 57.57万 - 项目类别:
Mitochondrial Sirtuin 3 in Parkinson's disease
线粒体 Sirtuin 3 在帕金森病中的作用
- 批准号:
10161872 - 财政年份:2019
- 资助金额:
$ 57.57万 - 项目类别:
Extracellular alpha-synuclein in Parkinson's Disease
帕金森病中的细胞外 α-突触核蛋白
- 批准号:
8234547 - 财政年份:2011
- 资助金额:
$ 57.57万 - 项目类别:
Extracellular alpha-synuclein in Parkinson's Disease
帕金森病中的细胞外 α-突触核蛋白
- 批准号:
8695502 - 财政年份:2011
- 资助金额:
$ 57.57万 - 项目类别: