Propagation of Lewy pathology in Parkinson's and related disorders

路易病理学在帕金森病及相关疾病中的传播

• 批准号: 10534194
• 负责人: Kelvin C Luk
• 金额: $ 46.54万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-13 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10534194
• 关键词: Acceleration; Address; Affect; Alzheimer' s Disease; Alzheimer' s disease patient; Animal Model; Animals; Antisense Oligonucleotides; Atlases; Autopsy; Biological; Brain; Brain Diseases; Brain Stem; Candidate Disease Gene; Cell Separation; Cells; Central Nervous System; Cytoplasm; Data; Dementia with Lewy Bodies; Deposition; Development; Disease; Disease Progression; Disease model; Distal; Dopamine; Early Diagnosis; Exposure to; Family; Funding; Gene Expression; Genes; Genetic; Histologic; Human; Impairment; Individual; Infectious Agent; Injections; Knock-in; Knock-in Mouse; Knock-out; Label; Lesion; Lewy Bodies; Lewy body pathology; Lewy neurites; Libraries; Link; Literature; Maps; Measures; Mediating; Methods; Modeling; Molecular; Molecular Profiling; Mus; Mutation; Nerve Degeneration; Neuroanatomy; Neurodegenerative Disorders; Neurologic Symptoms; Neurons; Oxidative Stress; Parkinson Disease; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Pattern; Peripheral Nervous System; Population; Predisposition; Prion Diseases; Process; Proteins; Rattus; Recombinants; Reporting; Resistance; SNCA gene; Site; Structure; Substantia nigra structure; Testing; Time; Tissues; Toxic effect; Tracer; Wild Type Mouse; alpha synuclein; brain cell; candidate marker; candidate validation; computerized tools; connectome; differential expression; dopaminergic neuron; gene expression database; genetic risk factor; human disease; in silico; in vivo; insight; knock-down; locomotor deficit; mathematical methods; mathematical model; misfolded protein; motor impairment; neuron loss; neuronal survival; nonhuman primate; novel; novel therapeutics; pars compacta; permissiveness; pre-formed fibril; risk variant; single-cell RNA sequencing; spatiotemporal; synucleinopathy; tool; transcriptome sequencing; virtual

The accumulation of misfolded proteins represents a common pathological mechanism of most major neurodegenerative disorders. Neuronal inclusions comprised of aggregated α-Synuclein (aSyn), known as Lewy bodies (LBs) and Lewy-neurites (LNs), represent a key histopathological feature of Parkinson's disease (PD) and a family of related disorders known as synucleinopathies, most notably Dementia with LBs (DLB). LBs are also a prominent feature in nearly half of Alzheimer's disease subjects. Mutations and amplifications in the SNCA gene encoding aSyn also cause familial forms of PD. Although a large body of histological and genetic evidence firmly indicate a correlation between aSyn accumulation and disease, it remains unclear how aSyn pathology actually forms and subsequently contributes to disease. We and others recently demonstrated that minute quantities of recombinant or patient-derived aSyn aggregates can catalyze the formation of toxic LBs/LNs in cultured neurons and healthy non-transgenic mice. In both human PD and animal models, this “seeded” aSyn pathology progressively propagates and spreads to neuroanatomically connected regions, reminiscent of prion diseases. Importantly, animals with LBs/LNs recapitulate the cardinal features of PD, including progressive loss of dopamine-producing neurons and locomotor deficits. This R01 renewal addresses several key biological questions posed by our earlier findings and combines novel molecular, in vivo, and computational tools to further understand how LBs/LNs form, propagate, and ultimately contribute to neurodegeneration and neurological symptoms. Aim 1 will identify at the neuron subtypes that develop LBs/LNs following inoculation with misfolded aSyn. By combining traditional histological methods with FACS-assisted single-neuron RNAseq, we will determine the molecular signatures associated with subpopulations that are vulnerable or resistant to LBs/LNs formation. Aim 2 will examine how PD genetic risk factors reported in the literature intersect with aSyn pathobiology, by testing the effect of knock-down or knock- in of individual genes on the formation of seeded pathology and neuronal survival. Candidates that significantly alter either will be confirmed in vivo using knock-out/knock-in mouse lines. Lastly, Aim 3 will integrate our molecular, genetic, and in vivo experimental data together with publicly available connectivity and gene- expression atlases to interrogate the mechanisms of pathological spread. Using recently developed mathematical approaches to describe infectious agent spread, we will develop in silico models to understand aSyn pathology formation and spread. Completion of these studies should provide valuable insights into the potential mechanisms by which aSyn contribute to the progression of PD and related disorders. Increased understanding of the pathogenesis of this and related synucleinopathies should ultimately result in earlier detection and disease-modifying therapies for these currently incurable disorders.

错误折叠蛋白的积累代表了大多数主要的常见病理机制