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Investigating Neuromelanin-Mediated Locus Coeruleus Neurodegeneration in a Novel Mouse Model of Parkinson's Disease

在帕金森病的新型小鼠模型中研究神经黑色素介导的蓝斑神经变性

基本信息

批准号：
10541704
负责人：
Alexa Faith Iannitelli
金额：
$ 4.56万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10541704
关键词：
Address Affect Affinity Chromatography Age Aging American Anxiety Astrocytes Autopsy Behavioral Behavioral Paradigm Binding Bradykinesia Brain Catecholamines Cell Nucleus Cells Chelation Therapy Cicatrix Communities Cytoplasm Cytoplasmic Granules Data Development Diagnosis Disease Electron Microscopy Enzymes Family Fellowship Functional disorder Genes Genetic Transcription Glean Hair Heavy Metals Human Immunohistochemistry Impaired cognition Incidence Individual Injections Intervention Levodopa Life Experience Lipids Longevity Macaca mulatta Mediating Melanins Membrane Mental Depression Messenger RNA Metals Methods Microscopy Molecular Molecular Profiling Molecular Target Monophenol Monooxygenase Motor Mus Nerve Degeneration Neurobiology Neurodegenerative Disorders Neuroimmune Neurons Neurosciences Neurotoxins Parkinson Disease Pathologic Pathology Pathway interactions Patients Peripheral Pharmacology Pharmacotherapy Phase Phenotype Pigments Play Population Postdoctoral Fellow Prevention Primates Production Public Health Quality of life RNA analysis Research Ribosomes Rodent Role Skin Sleep disturbances Structure Study models Substantia nigra structure Symptoms Technical Expertise Techniques Testing Time Tissues Toxic effect Toxin Training Transcript Transgenic Mice Translating Tremor United States Viral Viral Vector Work aged alpha synuclein anxiety-like behavior associated symptom behavioral impairment differential expression dopaminergic neuron eumelanin experience experimental study improved in vivo innovation insight locus ceruleus structure motor deficit motor symptom mouse model neuroinflammation neuromelanin neuropathology non-motor symptom nonhuman primate noradrenergic norepinephrine system novel novel strategies pheomelanin prevent response skills therapeutic target therapeutically effective transcriptome sequencing

项目摘要

Investigating neuromelanin-mediated locus coeruleus neurodegeneration in a novel mouse model of Parkinson’s disease Alexa Iannitelli Summary Parkinson’s disease (PD) is the second most common neurodegenerative disorder worldwide, and is characterized by motor and non-motor symptoms. The leading pharmacotherapy, levodopa, is only effective for treating the motor symptoms caused by dopamine (DA) neuron degeneration, while non-motor symptoms associated with noradrenergic dysfunction have grave consequences for the quality of life experienced by PD patients and are not alleviated by any currently available therapies. Thus, new research on PD neuropathology and treatment must consider the locus coeruleus (LC), the major central noradrenergic nucleus. The LC develops alpha-synuclein pathology prior to DA neurons in PD and is almost completely degenerated in later stage disease, but the molecular mechanisms responsible for its vulnerability are unknown. Along with substantia nigra DA neurons, the LC is the only structure in the brain that produces appreciable amounts of neuromelanin (NM), a dark brown cytoplasmic pigment. It has been proposed that these NM granules initially play a protective role by sequestering toxic catecholamine metabolites and heavy metals, but become harmful during aging and particularly in PD as they overwhelm cellular machinery and get released during neurodegeneration. Because rodents do not naturally produce NM, the study of this pigment has been mostly limited to human postmortem studies, and it has not been possible to experimentally address the role of NM in PD-associated LC pathology. However, I have adapted a viral-mediated approach for expression of human tyrosinase, the enzyme responsible for the development of melanin in skin cells, to promote NM production in rodent LC neurons. I found that pigment expression in the LC recapitulates key features of endogenous NM found in primates, including eumelanin and pheomelanin, lipid droplets, and a double-membrane encasement. By 10-weeks post-injection, mice display severe LC neurodegeneration and a robust neuroinflammatory response, resulting in astrocytic glial scarring. Behavioral consequences include hyperarousal, increased anxiety-like behavior, and cognitive impairment. These phenotypes reflect non-motor symptoms of PD, validating the utility of this model for studying the consequences of NM accumulation in the LC as it relates to neurodegenerative disease. During the F99 phase, I propose to expand these findings by employing the ribo-tagging technique Translating Ribosome Affinity Purification (TRAP) to investigate how changes in gene transcription relate to, and potentially underlie, NM-induced LC dysfunction and degeneration. In the K00 phase, I will apply the information gleaned from these studies to investigate potential mechanistic and pharmacological interventions in the hopes of mitigating toxic NM accumulation and subsequent neurodegeneration, in both the LC and SN. These studies will provide a comprehensive understanding of how NM contributes to the early vulnerability of catecholamine neurons in PD, and will help identify potential molecular targets for the prevention and treatment of this debilitating neurodegenerative disease.

在一种新型帕金森病小鼠模型中研究神经黑色素介导的蓝斑神经变性