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PINK 1对树突的调节：对PD/LBD的意义 项目摘要。 突触丢失是痴呆症的一个主要结构相关因素，并且在痴呆症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诱导的激酶1（PINK 1）可导致早发性PD和PD伴痴呆（PDD）。杂合子携带者 也表现出认知执行功能障碍和边缘皮质退化。由于PINK 1具有神经保护作用， 广泛的遗传和毒素为基础的神经变性模型，研究其在神经元中的功能， 提供对潜在治疗策略的见解。内源性PINK 1存在于线粒体和 胞质区室我们先前的研究表明，这些PINK 1库在调节细胞凋亡中发挥着不同的作用。 线粒体分裂-融合、线粒体自噬、钙稳态和树突形态发生。此外，损失 PINK 1的表达导致皮质和中脑神经元的树突简化。我们假设PINK 1 与胞质靶相互作用以调节神经元分化和突触树突复杂性。 使用质谱，我们鉴定了新的PINK 1相互作用蛋白，初步研究 涉及神经突延伸或神经元运输。我们将研究这些新的PINK 1相互作用的作用， 在调节树突发生和线粒体运输到树突使用初级皮质和中脑 神经元、分化的神经元细胞系和PINK 1敲除小鼠和对照小鼠。的潜在作用 磷酸化和PD连锁突变对PINK 1的这些神经元特异性功能的影响将 被分析。将测试上调下游通路组分的神经保护潜力。 在体外和Pink 1-/-小鼠中。更好地理解PINK 1驱动的新机制， 树突的简化可能会产生有价值的见解，在PD-LBD疾病谱的神经保护。