Evidence of Neurobiological Changes in the Presymptomatic PINK1 Knockout Rat
Evidence of Neurobiological Changes in the Presymptomatic PINK1 Knockout Rat
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DOI：
10.3233/jpd-171273
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发表时间：
2018-01-01
影响因子：
5.2
通讯作者：
Trivedi, Malav
中科院分区：
文献类型：
--
作者：
Ferris, Craig F.;Morrison, Thomas R.;Trivedi, Malav
背景资料：帕金森病（PD）的遗传模型与先进的成像技术相结合，可以阐明神经生物学疾病的进展，并有助于在临床症状出现之前识别早期生物标志物。PTEN诱导的推定激酶1（PINK 1）有助于保护神经元免受线粒体功能障碍，相关基因的突变是隐性家族性PD的危险因素。PINK 1基因敲除（KO）大鼠是一种新的家族性PD模型，在4月龄之前，其脑结构/功能以及行为的改变尚未被神经放射学表征。目的：利用磁共振成像技术鉴定PINK 1-/-大鼠3月龄时症状前PD的生物标志物。比先前报道的运动和认知功能障碍的迹象早一个月，这项研究结合了成像方式，包括使用注释的MRI大鼠脑图谱评估171个单独脑区的定量各向异性，以确定野生型和PINK 1-/-大鼠之间灰质改变的位点。嗅觉系统、下丘脑、丘脑、丘脑核和小脑的各向异性在实验组之间存在差异。分子分析显示，黑质、纹状体和小脑深部核的谷胱甘肽、ATP水平降低，氧化应激水平升高。线粒体基因编码复合体IV中的蛋白质，沿着与线粒体功能相关的mRNA水平和参与谷胱甘肽合成的基因减少。大脑结构的差异并没有与任何认知或运动impairment.Conclusions：这些数据揭示了早期的标记，并突出了新的大脑区域参与PD的病理在PINK 1-/-大鼠行为功能障碍发生之前。
Background: Genetic models of Parkinson's disease (PD) coupled with advanced imaging techniques can elucidate neurobiological disease progression, and can help identify early biomarkers before clinical signs emerge. PTEN-induced putative kinase 1 (PINK1) helps protect neurons from mitochondrial dysfunction, and a mutation in the associated gene is a risk factor for recessive familial PD. The PINK1 knockout (KO) rat is a novel model for familial PD that has not been neuroradiologically characterized for alterations in brain structure/function, alongside behavior, prior to 4 months of age.Objective: To identify biomarkers of presymptomatic PD in the PINK1 -/- rat at 3 months using magnetic resonance imaging techniques.Methods: At postnatal weeks 12-13; one month earlier than previously reported signs of motor and cognitive dysfunction, this study combined imaging modalities, including assessment of quantitative anisotropy across 171 individual brain areas using an annotated MRI rat brain atlas to identify sites of gray matter alteration between wild-type and PINK1 -/- rats.Results: The olfactory system, hypothalamus, thalamus, nucleus accumbens, and cerebellum showed differences in anisotropy between experimental groups. Molecular analyses revealed reduced levels of glutathione, ATP, and elevated oxidative stress in the substantia nigra, striatum and deep cerebellar nuclei. Mitochondrial genes encoding proteins in Complex IV, along with mRNA levels associated with mitochondrial function and genes involved in glutathione synthesis were reduced. Differences in brain structure did not align with any cognitive or motor impairment.Conclusions: These data reveal early markers, and highlight novel brain regions involved in the pathology of PD in the PINK1 -/- rat before behavioral dysfunction occurs.