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

线粒体激酶PINK1对树突状细胞的调节：与PD/LBD的关系 项目总结。 突触丢失是痴呆症的主要结构相关性，在 帕金森氏病(PD)-路易体痴呆(LBD)疾病谱。常染色体隐性突变 PTEN诱导的蛋白激酶1(PINK1)可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。因为PINK1具有神经保护作用 广泛的遗传和基于毒素的神经变性模型，研究其在神经元中的功能可能 提供对潜在治疗策略的见解。内源性PINK1同时存在于线粒体和 胞质隔间。我们先前的研究表明，这些PINK1池在调节中扮演着不同的角色 线粒体分裂融合、有丝分裂、钙稳态和树突状形态发生。此外，损失 PINK1的表达导致皮质和中脑神经元树突简化。我们假设PINK1 与胞浆靶点相互作用，调节神经元分化和突触树突复杂性。 利用质谱仪，我们鉴定了新的与PINK1相互作用的蛋白质，并对其进行了初步研究 牵涉到轴突延伸或神经元运输。我们将研究这些新的PINK1相互作用的作用 利用初级皮质和中脑调节树突的发生和线粒体向树突的运输 神经元、分化的神经元细胞系和PINK1基因敲除小鼠和对照小鼠。的潜在作用 PINK1 Will的磷酸化及PD连锁突变对这些神经元特化功能的影响 被分析。将测试上调下游通路成分的神经保护潜力 在体外和在PINK1-/-小鼠体内。更好地理解PINK1驱动的新机制，以防止 树突状简化可能为PD-LBD疾病谱中的神经保护提供有价值的见解。

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.