Departamento de Patología, Facultad de Medicina e Instituto de Genética, Universidad Nacional de Colombia, Bogotá DC, Colombia.
J Mol Neurosci. 2019 Dec;69(4):570-579. doi: 10.1007/s12031-019-01385-x. Epub 2019 Sep 5.
PTEN-induced kinase 1 (PINK1) mutations can cause early-onset Parkinson's disease and patients are likely to develop cognitive decline, depression, and dementia. Several neurophysiological studies have demonstrated PINK1 deficiency impairs striatal and hippocampal presynaptic plasticity. Dendritic spine postsynaptic abnormalities are common in neurological diseases; however, whether PINK1 silencing modifies dendritic spine dynamics of hippocampal neurons is unclear. To address this question, confocal images of mouse cultured hippocampal neurons transfected with plasmids to silence PINK1 were analyzed. These studies revealed that PINK1 silencing increased density of thin spines and reduced head size of stubby spines. Immunoblotting analysis uncovered that PINK1 silencing decreased expression of postsynaptic density proteins (PSD95 and Shank) and glutamate receptors (NR2B and mGluR5). We also found PINK1 silencing regulated dendritic spine morphology by actin regulatory proteins (RhoGAP29 and ROCK2) and regulated neuronal survival by decreased Akt activation. These results suggest PINK1 may regulate postsynaptic plasticity in hippocampal neurons generating presymptomatic alterations in dendritic spines that eventually could lead to the neurodegeneration and cognitive decline often seen in Parkinson's disease.
PTEN 诱导激酶 1 (PINK1) 突变可导致早发性帕金森病，患者可能出现认知能力下降、抑郁和痴呆。多项神经生理学研究表明，PINK1 缺乏会损害纹状体和海马的突触前可塑性。树突棘突触后异常在神经退行性疾病中很常见；然而，PINK1 沉默是否会改变海马神经元的树突棘动力学尚不清楚。为了解决这个问题，分析了转染沉默 PINK1 质粒的培养的海马神经元的共聚焦图像。这些研究表明，PINK1 沉默增加了薄棘的密度，并减少了短棘的头部大小。免疫印迹分析显示，PINK1 沉默降低了突触后密度蛋白（PSD95 和 Shank）和谷氨酸受体（NR2B 和 mGluR5）的表达。我们还发现，PINK1 沉默通过肌动蛋白调节蛋白（RhoGAP29 和 ROCK2）调节树突棘形态，并通过降低 Akt 激活来调节神经元存活。这些结果表明，PINK1 可能调节海马神经元的突触后可塑性，导致树突棘出现前驱性改变，最终可能导致帕金森病中经常出现的神经退行性变和认知能力下降。
