Predictors of prodromal Parkinson's disease in young adult Pink1-/- rats.
Predictors of prodromal Parkinson's disease in young adult Pink1-/- rats.
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DOI：
10.3389/fnbeh.2022.867958
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发表时间：
2022
影响因子：
3
通讯作者：
Kelm-Nelson, Cynthia A.
中科院分区：
文献类型：
--
作者：
Lechner, Sarah A.;Welsch, Jacob M.;Pahapill, Natalie K.;Kaldenberg, Taylor A. R.;Regenbaum, Amy;Kelm-Nelson, Cynthia A.
帕金森病 (PD) 是一种进行性退行性疾病，影响全球近 1000 万人。标志性肢体运动体征和多巴胺耗竭已得到充分研究；然而，很少有研究评估早期、前驱生物学。 Pink1−/− 大鼠是 PD 线粒体功能障碍的啮齿动物模型，表现出早期行为缺陷，包括声音交流和焦虑，并在成年中后期（6-12 个月大）出现进展。然而，导致前驱功能障碍的生物学途径和机制尚不清楚。本研究调查了年轻成年期（2 个月大）的 Pink1−/− 大鼠。对 Pink1−/− 大鼠和野生型 (WT) 对照组的混合性别组进行肢体运动、焦虑和发声运动行为的分析。基于成年后期的遗传工作，定制的 NanoString CodeSet 用于探测与脑干和声带肌肉内的疾病途径和炎症有关的基因的上调。总之，数据显示了肢体运动、焦虑和声音运动行为的性别和基因型差异。具体而言，与雄性 Pink1−/− 大鼠相比，雌性 Pink1−/− 大鼠表现出较少的焦虑样行为，并且与雄性大鼠相比，雌性 Pink1−/− 大鼠表现出增强的运动活动。 Pink1−/− 大鼠还表现出所有声学参数的前驱超声发声功能障碍，并且强度（响度）和峰值频率存在性别差异。这些数据证明了 Pink1−/− 模型中表型的差异。 Tuba1c 转录水平被确定为与 2 个月龄超声发声负相关的关键标志物。识别 Tuba1c 等基因可能有助于确定 Pink1−/− 大鼠 PD 病理学的早期预测因素，并作为未来药物治疗研究的目标。
Parkinson’s disease (PD) is a progressive, degenerative disease that affects nearly 10 million people worldwide. Hallmark limb motor signs and dopamine depletion have been well studied; however, few studies evaluating early stage, prodromal biology exist. Pink1−/− rats, a rodent model of PD mitochondrial dysfunction, exhibit early stage behavioral deficits, including vocal communication and anxiety, that progress during mid-to-late adulthood (6–12 months of age). Yet, the biological pathways and mechanisms that lead to prodromal dysfunction are not well understood. This study investigated the Pink1−/− rat in young adulthood (2 months of age). Mixed sex groups of Pink1−/− rats and wildtype (WT) controls were assayed for limb motor, anxiety, and vocal motor behaviors. A customized NanoString CodeSet, based on genetic work in later adulthood, was used to probe for the up regulation of genes involved in disease pathways and inflammation within the brainstem and vocal fold muscle. In summary, the data show sex- and genotype-differences in limb motor, anxiety, and vocal motor behaviors. Specifically, female Pink1−/− rats demonstrate less anxiety-like behavior compared to male Pink1−/− rats and female rats show increased locomotor activity compared to male rats. Pink1−/− rats also demonstrate prodromal ultrasonic vocalization dysfunction across all acoustic parameters and sex differences were present for intensity (loudness) and peak frequency. These data demonstrate a difference in phenotype in the Pink1−/− model. Tuba1c transcript level was identified as a key marker negatively correlated to ultrasonic vocalization at 2 months of age. Identifying genes, such as Tuba1c, may help determine early predictors of PD pathology in the Pink1−/− rat and serve as targets for future drug therapy studies.
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