Alpha-synuclein deficiency affects brain Foxp1 expression and ultrasonic vocalization

Alpha-synuclein is an abundant protein implicated in synaptic function and plasticity, but the molecular mechanism of its action is not understood. Missense mutations and gene duplication/triplication events result in Parkinson's disease, a neurodegenerative disorder of old age with impaired movement and emotion control. Here, we systematically investigated the striatal as well as the cerebellar transcriptome profile of alpha-synuclein-deficient mice via a genome-wide microarray survey in order to gain hypothesis-free molecular insights into the physiological function of alpha-synuclein. A genotype-dependent, specific and strong downregulation of forkhead box P1 (Foxp1) transcript levels was observed in all brain regions from postnatal age until old age and could be validated by qPCR. In view of the co-localization and heterodimer formation of FOXP1 with FOXP2, a transcription factor with a well established role for vocalization, and the reported regulation of both alpha-synuclein and FOXP2 expression during avian song learning, we performed a detailed assessment of mouse movements and vocalizations in the postnatal period. While there was no difference in isolation-induced behavioral activity in these animals, the alpha-synuclein-deficient mice exhibited an increased production of isolation-induced ultrasonic vocalizations (USVs). This phenotype might also reflect the reduced expression of the anxiety-related GABA-A receptor subunit gamma 2 (Gabrg2) we observed. Taken together, we identified an early behavioral consequence of alpha-synuclein deficiency and accompanying molecular changes, which supports the notion that the neural connectivity of sound or emotion control systems is affected. Factorial design comparing SNCA knock-out mice with wild type littermates in two different tissues (striatum, cerebellum) at two different timepoints (6 and 21 month)α-突触核蛋白（Alpha-synuclein）是一种丰度较高的蛋白质，参与突触功能与突触可塑性调控，但其发挥作用的分子机制尚未明确。错义突变以及基因重复/三倍化事件可引发帕金森病（Parkinson's disease）——一种以运动与情绪控制受损为特征的老年神经退行性疾病。本研究通过全基因组芯片（genome-wide microarray）检测，系统分析了α-突触核蛋白敲除小鼠的纹状体（striatum）与小脑（cerebellum）转录组（transcriptome）特征，以期获得无预设假说的分子层面见解，解析α-突触核蛋白的生理功能。研究观测到，从出生后直至老年的所有脑区中，叉头框P1（forkhead box P1, Foxp1）的转录本水平均出现了基因型依赖的特异性显著下调，该结果可通过实时定量PCR（quantitative PCR, qPCR）验证。鉴于FOXP1与FOXP2存在共定位并形成异二聚体，且FOXP2作为一种在发声调控中功能已得到充分证实的转录因子，已有研究报道在鸟类鸣唱学习（avian song learning）过程中，α-突触核蛋白与FOXP2的表达均受到调控，因此我们对小鼠出生后的运动行为与发声情况开展了详细评估。尽管此类小鼠在隔离诱导的行为活动上无显著差异，但α-突触核蛋白敲除小鼠的隔离诱导超声发声（ultrasonic vocalizations, USVs）产量显著升高。该表型可能也与我们观测到的焦虑相关γ-氨基丁酸A型（GABA_A）受体亚基γ2（Gabrg2）表达下调有关。综上，本研究鉴定出了α-突触核蛋白缺失的早期行为表型及其伴随的分子变化，这支持了「声音或情绪调控系统的神经连接受到影响」这一观点。本研究采用析因设计（factorial design），在6月龄与21月龄两个不同时间点下，对比SNCA基因敲除小鼠与其野生型同窝幼崽在纹状体与小脑两种组织中的转录组特征。