Department of Pathology, Division of Neuropathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213.
Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania 15260.
J Neurosci. 2022 Oct 12;42(41):7848-7860. doi: 10.1523/JNEUROSCI.0785-22.2022. Epub 2022 Sep 7.
Mutations in PTEN-induced kinase 1 (PINK1) contribute to autosomal recessive Parkinson's disease with cognitive and neuropsychiatric comorbidities. Disturbances in dendritic and spine architecture are hallmarks of neurodegenerative and neuropsychiatric conditions, but little is known of the impact of PINK1 on these structures. We used mice to study the role of endogenous PINK1 in regulating dendritic architecture, spine density, and spine maturation. cortical neurons of unknown sex showed decreased dendritic arborization, affecting both apical and basal arbors. Dendritic simplification in neurons was primarily driven by diminished branching with smaller effects on branch lengths. neurons showed reduced spine density with a shift in morphology to favor filopodia at the expense of mushroom spines. Electrophysiology revealed significant reductions in miniature EPSC (mEPSC) frequency in neurons, consistent with the observation of decreased spine numbers. Transfecting with human PINK1 rescued changes in dendritic architecture, in thin, stubby, and mushroom spine densities, and in mEPSC frequency. Diminished spine density was also observed in Golgi-Cox stained adult male brains. Western blot study of brains of either sex revealed reduced phosphorylation of NSFL1 cofactor p47, an indirect target of PINK1. Transfection of neurons with a phosphomimetic p47 plasmid rescued dendritic branching and thin/stubby spine density with a partial rescue of mushroom spines, implicating a role for PINK1-regulated p47 phosphorylation in dendrite and spine development. These findings suggest that PINK1-dependent synaptodendritic alterations may contribute to the risk of cognitive and/or neuropsychiatric pathologies observed in PINK1-mutated families. Loss of PINK1 function has been implicated in both familial and sporadic neurodegenerative diseases. Yet surprisingly little is known of the impact of PINK1 loss on the fine structure of neurons. Neurons receive excitatory synaptic signals along a complex network of projections that form the dendritic tree, largely at tiny protrusions called dendritic spines. We studied cortical neurons and brain tissues from mice lacking PINK1. We discovered that PINK1 deficiency causes striking simplification of dendritic architecture associated with reduced synaptic input and decreased spine density and maturation. These changes are reversed by reintroducing human PINK1 or one of its downstream mediators into PINK1-deficient mouse neurons, indicating a conserved function, whose loss may contribute to neurodegenerative processes.
PTEN 诱导的激酶 1 (PINK1) 突变导致常染色体隐性遗传帕金森病伴认知和神经精神共病。树突和棘突结构的紊乱是神经退行性和神经精神疾病的标志，但人们对 PINK1 对这些结构的影响知之甚少。我们使用 小鼠来研究内源性 PINK1 在调节树突结构、棘突密度和棘突成熟中的作用。 未明性别的皮质神经元表现出树突分支减少，影响顶树突和基底树突。 神经元中的树突简化主要是由于分支减少，对分支长度的影响较小。 神经元的棘突密度降低，形态向有利于丝状伪足而不是蘑菇状棘突的方向转变。电生理学研究表明， 神经元中的微小 EPSC（mEPSC）频率显著降低，与棘突数量减少的观察结果一致。转染人 PINK1 可挽救树突结构、薄棘突、短棘突和蘑菇棘突密度以及 mEPSC 频率的变化。在成年雄性 的高尔基-考克斯染色大脑中也观察到棘突密度降低。对任何性别的 大脑的 Western blot 研究显示，NSFL1 辅助因子 p47 的磷酸化减少，p47 是 PINK1 的间接靶点。用磷酸化模拟 p47 质粒转染 神经元可挽救树突分支和薄/短棘突密度，并部分挽救蘑菇棘突，表明 PINK1 调节的 p47 磷酸化在树突和棘突发育中起作用。这些发现表明，PINK1 依赖性突触-树突改变可能导致 PINK1 突变家族中观察到的认知和/或神经精神病理风险增加。PINK1 功能丧失与家族性和散发性神经退行性疾病有关。然而，人们对 PINK1 缺失对神经元精细结构的影响知之甚少。神经元沿着形成树突的复杂网络接收兴奋性突触信号，主要在称为树突棘的微小突起上。我们研究了缺乏 PINK1 的皮质神经元和脑组织。我们发现 PINK1 缺乏导致树突结构明显简化，与突触输入减少和棘突密度和成熟度降低有关。通过将人 PINK1 或其下游介质之一重新引入 PINK1 缺陷型小鼠神经元中，这些变化得到逆转，表明存在保守功能，其缺失可能导致神经退行性过程。
