Mitochondrial protection of a GDNF propeptide

GDNF 前肽的线粒体保护

• 批准号: 8259428
• 负责人: Luke H Bradley
• 金额: $ 7.43万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8259428
• 关键词: Affect; Agriculture; American; Amino Acids; Attention; Bioenergetics; Biological Response Modifier Therapy; Bradykinesia; Brain; Cell Culture Techniques; Cell Death; Cell Line; Cells; Chronic; Complex; Data; Development; Disadvantaged; Dopaminergic Cell; Endopeptidases; Etiology; Evaluation; Event; Exhibits; Exposure to; Family; Future; Goals; Growth Factor; Hand; Individual; Measures; Mitochondria; Modeling; Names; Nervous system structure; Neurobiology; Neurotoxins; Occupational; Parkinson Disease; Parkinsonian Disorders; Pathogenesis; Patients; Peptides; Pilot Projects; Posture; Predisposition; Property; Proteins; Proteomics; Rattus; Research; Respiration; Respiratory Chain; Rest; Site; Stress; Symptoms; Testing; Therapeutic; Therapeutic Agents; Toxic Environmental Substances; Toxin; Tremor; aged; base; clinical application; dopaminergic neuron; equilibration disorder; glial cell-line derived neurotrophic factor; mitochondrial dysfunction; nervous system disorder; neurotrophic factor; novel; protective effect; public health relevance; respiratory; response; restoration

DESCRIPTION (provided by applicant): Mitochondrial dysfunction has been identified as one of the key players in Parkinson's disease (PD) pathogenesis. While the etiology is unknown in most cases, the development of progressive parkinsonian symptoms has been shown in patients following exposure to various environmental and occupational toxins. Numerous studies demonstrate that these neurotoxins specifically inhibit the mitochondrial respiratory chain complexes of dopaminergic neurons, which initiates a cascade of events ultimately leading to cell death. Furthermore, the susceptibility to environmental neurotoxins is increased in the aged nervous system. Thus for the long-term treatment of PD and parkinsonian symptoms, therapeutic strategies are needed that not only restore dopaminergic neuron function, but also provide mitochondrial protection and restoration from various stresses, including environmental toxin exposure. In the past, neurotrophic growth factors have received considerable attention as potential therapeutic agents for neurological disorders. However, the clinical application of these native molecules has not advanced primarily due to pharmacological disadvantages and challenges associated with directly delivering large protein molecules to the brain. The emergence of physiologically functional propeptides from the neurotrophic factor family provides a wealth of novel, smaller sequences for biotherapeutic exploration and evaluation. Examination of the glial cell line-derived neurotrophic factor (GDNF) prosequence predicts internal dibasic endopeptidase sites that would yield a smaller, amidated eleven amino acid residue peptide named dopamine neuron stimulating peptide-11 (DNSP-11). Recent evaluation of DNSP-11 has shown that it exhibits similar GDNF-like neurotrophic responses in normal and parkinsonian rat models. However, cell culture and proteomic pull-down data suggest that DNSP-11 functions differently than mature GDNF; leading to our hypothesis that DNSP-11's neurobiological actions are through the mitochondria. The research outlined in the current proposal will measure DNSP-11's bioenergetic and protective effects, in the MN9D dopaminergic cell line, from toxins that specifically target the mitochondrial respiratory complexes. The information obtained in this study will further our understanding of this propeptide's neurobiological activity and provide the basis for future evaluation and biotherapeutic development of DNSP-11. PUBLIC HEALTH RELEVANCE: Parkinson's disease (PD), a chronic neurological disorder that affects over 1 million Americans, is characterized by stooped posture, balance impairments, rigidity, resting hand tremors, and bradykinesia. While the cause of PD is largely unknown, parkinsonian symptoms have been shown to develop following long-term exposure to common environmental toxins that specifically target the mitochondria of dopamine neurons. The goal of this pilot project is to investigate the neuroprotective properties of a novel neurotrophic propeptide, DNSP-11, from mitochondrial-specific toxins to pave the way for its downstream evaluation as a potential PD therapeutic.

描述（由申请人提供）：线粒体功能障碍已被确定为帕金森病（PD）发病机制的关键因素之一。虽然病因在大多数情况下是未知的，但在暴露于各种环境和职业毒素后的患者中已显示出进展性帕金森病症状的发展。许多研究表明，这些神经毒素特异性抑制多巴胺能神经元的线粒体呼吸链复合物，这引发了一系列事件，最终导致细胞死亡。此外，对环境神经毒素的敏感性在老年神经系统中增加。因此，对于PD和帕金森病症状的长期治疗，需要不仅恢复多巴胺能神经元功能，而且还提供线粒体保护和从各种应激（包括环境毒素暴露）恢复的治疗策略。 在过去，神经营养生长因子作为神经系统疾病的潜在治疗剂受到了相当大的关注。然而，这些天然分子的临床应用尚未取得进展，主要是由于与直接将大蛋白质分子递送到大脑相关的药理学缺点和挑战。从神经营养因子家族的生理功能的前肽的出现提供了丰富的新的，更小的序列生物学的探索和评价。胶质细胞源性神经营养因子（GDNF）前体序列的检查预测内部的二元内肽酶位点，将产生一个更小的，酰胺化的11个氨基酸残基肽命名为多巴胺神经元刺激肽-11（DNSP-11）。最近对DNSP-11的评估表明，它在正常和帕金森大鼠模型中表现出类似的GDNF样神经营养反应。然而，细胞培养和蛋白质组下拉数据表明，DNSP-11的功能不同于成熟的GDNF;导致我们的假设，DNSP-11的神经生物学作用是通过线粒体。目前提案中概述的研究将测量DNSP-11在MN 9D多巴胺能细胞系中对专门针对线粒体呼吸复合物的毒素的生物能量和保护作用。本研究的结果将为深入了解DNSP-11前肽的神经生物学活性提供依据，并为DNSP-11的生物活性评价和生物活性开发提供依据。 公共卫生相关性：帕金森病（PD）是一种慢性神经系统疾病，影响超过100万美国人，其特征在于弯腰姿势、平衡障碍、僵硬、静止手震颤和运动迟缓。虽然PD的原因在很大程度上是未知的，但帕金森症状已被证明是在长期暴露于常见的环境毒素后发展的，这些毒素专门针对多巴胺神经元的线粒体。该试点项目的目标是研究一种新的神经营养前肽DNSP-11的神经保护特性，从神经特异性毒素中，为其作为潜在的PD治疗剂的下游评估铺平道路。