Dendrite regulation by the mitochondrial kinase PINK1: Implications for PD/LBD

线粒体激酶 PINK1 的树突调节：对 PD/LBD 的影响

• 批准号: 9973247
• 负责人: Charleen T Chu
• 金额: $ 45.61万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9973247
• 关键词: Affect; Autophagocytosis; Axon; Binding; Binding Proteins; Biochemical; Brain; Brain Diseases; Calcium; Cell Line; Cells; Cognitive; Communication; Complex; Cytosol; Data; Dementia; Dendrites; Dendritic Spines; Disease; Dynein ATPase; Elements; Executive Dysfunction; Exhibits; Genetic; Half-Life; Health; Homeostasis; Human; ING1 gene; Impaired cognition; In Vitro; Knock-out; Length; Lewy Body Dementia; Link; Maintenance; Mass Spectrum Analysis; Mediating; Membrane; Methods; Midbrain structure; Mitochondria; Modeling; Molecular; Morphogenesis; Morphology; Mus; Mutation; N-terminal; Nerve Degeneration; Neurites; Neuronal Differentiation; Neuronal Injury; Neurons; PTEN gene; Parkinson Disease; Parkinson' s Dementia; Pathway interactions; Patients; Phenotype; Phosphorylation; Phosphorylation Site; Phosphotransferases; Play; Process; Proteins; Proteomics; Public Health; Quality Control; Regulation; Role; Signal Transduction; Structure; Surface; Synapses; Testing; Therapeutic; Thinness; Toxin; Vertebral column; base; brain cell; brain tissue; cofactor; density; design; disease-causing mutation; early onset; frontal lobe; in vitro testing; in vivo; insight; live cell imaging; loss of function mutation; mitochondrial processing peptidase; mutant; neuronal transport; neuroprotection; novel; parkin gene/protein; prevent; recruit; synaptic function; valosin-containing protein

Dendrite regulation by the mitochondrial kinase PINK1: Implications for PD/LBD PROJECT SUMMARY. Synaptic loss is a major structural correlate of dementia, and reduced spine density is observed in the Parkinson's disease (PD)-Lewy body dementia (LBD) disease spectrum. Autosomal recessive mutations in PTEN-induced kinase 1 (PINK1) cause early-onset PD and PD with dementia (PDD). Heterozygous carriers also exhibit cognitive-executive dysfunction and limbic-cortical degeneration. As PINK1 is neuroprotective in a wide range of genetic and toxin-based models of neurodegeneration, studying its function in neurons may offer insights into potential therapeutic strategies. Endogenous PINK1 exists in both mitochondrial and cytosolic compartments. Our prior studies show that these pools of PINK1 play divergent roles in regulating mitochondrial fission-fusion, mitophagy, calcium homeostasis and dendritic morphogenesis. Moreover, loss of PINK1 results in dendritic simplification in cortical and midbrain neurons. We hypothesize that PINK1 interacts with cytosolic targets to regulate neuron differentiation and synaptodendritic complexity. Using mass spectrometry, we identified novel PINK1-interacting proteins, which preliminary studies implicate in neurite extension or neuronal transport. We will study the role of these novel PINK1 interactions in regulating dendritogenesis and mitochondrial transport into dendrites using primary cortical and midbrain neurons, differentiated neuronal cell lines and PINK1 knockout and control mice. The potential role of phosphorylation and the impact of PD-linked mutations on these neuron-specialized functions of PINK1 will be analyzed. The neuroprotective potential of upregulating downstream pathway components will be tested in vitro and in Pink1-/- mice. A better understanding of novel PINK1-driven mechanisms that act to prevent dendritic simplification may yield valuable insights for neuroprotection in the PD-LBD disease spectrum.

线粒体激酶pink1的树突调节：对PD/LBD的影响 项目摘要。 突触损失是痴呆症的主要结构相关性，并且在脊柱密度下降低 帕金森氏病（PD） - Lewy身体痴呆（LBD）病谱。常染色体隐性突变 PTEN诱导的激酶1（PINK1）引起早发PD和痴呆症（PDD）。杂合载体 还表现出认知 - 执行功能障碍和边缘 - 皮层变性。因为pink1在 多种基于遗传和毒素的神经变性模型，研究其在神经元中的功能可能 提供有关潜在治疗策略的见解。内源性pink1都存在于线粒体和 胞质室。我们先前的研究表明，这些pink1池在调节中扮演不同的角色 线粒体裂变，线粒体，钙稳态和树突形态发生。而且，损失 PINK1的含量导致皮质和中脑神经元的树突状简化。我们假设pink1 与胞质靶标相互作用，以调节神经元分化和突触的复杂性。 使用质谱法，我们确定了新型的Pink1相互作用蛋白，这些蛋白是初步研究 与神经突延伸或神经元转运有关。我们将研究这些新颖的Pink1相互作用的作用 在调节树突生成和线粒体转运中，使用原发性皮质和中脑运输到树突中 神经元，分化的神经元细胞系以及PINK1敲除和对照小鼠。潜在的作用 PD连接突变对PINK1的这些神经元特异性功能的磷酸化和PD连接突变的影响将 可以分析。将测试上调下游途径成分的神经保护潜力 体外和pink1 - / - 小鼠。更好地理解以防止粉红色1驱动的新型机制 树突状的简化可能会在PD-LBD疾病谱系中产生有价值的神经保护见解。