Parkinson’s disease (PD) is a degenerative disease with early-stage pathology hypothesized to manifest in brainstem regions. Vocal deficits, including soft, monotone speech, result in significant clinical and quality of life issues and are present in 90% of PD patients; yet the underlying pathology mediating these significant voice deficits is unknown. The Pink1−/− rat is a valid model of early-onset PD that presents with analogous vocal communication deficits. Previous work shows abnormal α-synuclein protein aggregation in the periaqueductal gray (PAG), a brain region critical and necessary to the modulation of mammalian vocal behavior. In this study, we used high-throughput RNA sequencing to examine gene expression within the PAG of both male and female Pink1−/− rats as compared to age-matched wildtype controls. We used a bioinformatic approach to (1) test the hypothesis that loss of Pink1 in the PAG will influence the differential expression of genes that interact with Pink1, (2) highlight other key genes that relate to this type of Mendelian PD, and (3) catalog molecular targets that may be important for the production of rat vocalizations. Knockout of the Pink1 gene resulted in differentially expressed genes for both male and female rats that also mapped to human PD datasets. Pathway analysis highlighted several significant metabolic pathways. Weighted gene co-expression network analysis (WGCNA) was used to identify gene nodes and their interactions in (A) males, (B) females, and (C) combined-sexes datasets. For each analysis, within the module containing the Pink1 gene, Pink1 itself was the central node with the highest number of interactions with other genes including solute carriers, glutamate metabotropic receptors, and genes associated with protein localization. Strong connections between Pink1 and Krt2 and Hfe were found in both males and female datasets. In females a number of modules were significantly correlated with vocalization traits. Overall, this work supports the premise that gene expression changes in the PAG may contribute to the vocal deficits observed in this PD rat model. Additionally, this dataset identifies genes that represent new therapeutic targets for PD voice disorders.

中文翻译：

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在Pink1基因敲除大鼠中，导水管周围灰色组织中的基因表达与人的声音行为和早期发作的帕金森病有关。

帕金森氏病（PD）是一种退行性疾病，据认为其早期病理表现在脑干区域。90％的PD患者中存在包括软，单调语音在内的声音缺陷，导致严重的临床和生活质量问题；然而，尚不清楚介导这些明显语音缺陷的潜在病理学。Pink1-/-大鼠是早期发作PD的有效模型，其表现为相似的语音交流障碍。先前的工作显示了导水管周围灰色（PAG）中异常的α-突触核蛋白蛋白质聚集，PAG是大脑区域，对调节哺乳动物的声音行为至关重要且必不可少。在这项研究中，我们使用高通量RNA测序来检查与年龄匹配的野生型对照相比，雄性和雌性Pink1-/-大鼠的PAG中的基因表达。我们使用生物信息学方法来（1）检验以下假设，即PAG中Pink1的缺失将影响与Pink1相互作用的基因的差异表达，（2）突出显示与此类孟德尔PD相关的其他关键基因，以及（3 ）列出可能对大鼠发声产生重要作用的分子靶标。敲除Pink1基因会导致雄性和雌性大鼠差异表达的基因，这些基因也映射到人类PD数据集。途径分析突出了几种重要的代谢途径。加权基因共表达网络分析（WGCNA）用于鉴定（A）雄性，（B）雌性和（C）组合性行为数据集中的基因节点及其相互作用。对于每个分析，在包含Pink1基因的模块中，Pink1本身是与其他基因（包括溶质载体，谷氨酸代谢型受体以及与蛋白质定位相关的基因）相互作用次数最多的中心节点。在男性和女性数据集中都发现了Pink1与Krt2和Hfe之间的紧密联系。在女性中，许多模块与发声特征显着相关。总的来说，这项工作支持了一个前提，即PAG中基因表达的变化可能导致了在该PD大鼠模型中观察到的声音缺陷。此外，该数据集还鉴定了代表PD语音障碍新治疗靶点的基因。在女性中，许多模块与发声特征显着相关。总的来说，这项工作支持了一个前提，即PAG中的基因表达变化可能导致了在该PD大鼠模型中观察到的声音缺陷。此外，该数据集还鉴定了代表PD语音障碍新治疗靶点的基因。在女性中，许多模块与发声特征显着相关。总的来说，这项工作支持了一个前提，即PAG中的基因表达变化可能导致了在该PD大鼠模型中观察到的声音缺陷。此外，该数据集还鉴定了代表PD语音障碍新治疗靶点的基因。