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: 10199062
• 负责人: Charleen T Chu
• 金额: $ 45.04万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10199062
• 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一个主要结构相关性，并且在神经元中观察到脊柱密度降低。 帕金森病（PD）-路易体痴呆（LBD）疾病谱。常染色体隐性突变 PTEN 诱导激酶 1 (PINK1) 会导致早发性帕金森病和帕金森病伴痴呆 (PDD)。杂合子携带者 还表现出认知执行功能障碍和边缘皮质变性。由于 PINK1 具有神经保护作用 广泛的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会 提供对潜在治疗策略的见解。内源性 PINK1 存在于线粒体和 胞质区室。我们之前的研究表明，这些 PINK1 库在调节 线粒体裂变融合、线粒体自噬、钙稳态和树突形态发生。而且，损失 PINK1 的表达导致皮质和中脑神经元的树突简化。我们假设 PINK1 与细胞质靶标相互作用，调节神经元分化和突触树突复杂性。 使用质谱法，我们鉴定了新型 PINK1 相互作用蛋白，初步研究 涉及神经突延伸或神经元运输。我们将研究这些新颖的 PINK1 相互作用的作用 使用初级皮质和中脑调节树突发生和线粒体转运至树突 神经元、分化神经元细胞系以及 PINK1 敲除小鼠和对照小鼠。的潜在作用 PINK1 的磷酸化和 PD 相关突变对这些神经元特异性功能的影响将 进行分析。将测试上调下游通路成分的神经保护潜力 体外和 Pink1-/- 小鼠中。更好地理解 PINK1 驱动的新颖机制，以防止 树突简化可能会为 PD-LBD 疾病谱中的神经保护提供有价值的见解。