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对树突的调节：对PD/LBD的影响