Atp13a2 expression in the periaqueductal gray is decreased in the Pink1 -/- rat model of Parkinson disease.
Atp13a2 expression in the periaqueductal gray is decreased in the Pink1 -/- rat model of Parkinson disease.
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DOI：
10.1016/j.neulet.2016.04.003
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发表时间：
2016-05-16
影响因子：
2.5
通讯作者：
Ciucci MR
中科院分区：
文献类型：
--
作者：
Kelm-Nelson CA;Stevenson SA;Ciucci MR
言语交流障碍在帕金森病（PD）中很常见。广泛的α -突触核蛋白病理是家族性和散发性PD之间的共同联系，最近基于家族遗传联系的遗传大鼠模型增加了探索发声缺陷及其相关神经病理的机会。具体来说，Pink1基因敲除（−/−）大鼠在8月龄时出现早期进行性运动缺陷，包括明显的声音缺陷。此外，与年龄匹配的未受影响野生型（WT）对照相比，该大鼠模型表现出α -突触核蛋白病理。在脑干中，脑管周围灰质（PAG）是参与协调情绪和意志控制发声的区域。在这里，我们研究了与WT相比，Pink1−/−大鼠8月龄PAG内基因表达的变化。我们的数据表明，Pink1−/−大鼠α -突触核蛋白mRNA表达水平与WT相当。然而，Pink1−/−大鼠的Atp13a2水平显著降低，这是一种跨膜溶酶体p5型atp酶，提示观察到的异常聚集的潜在机制。我们发现葡萄糖脑苷酶（Gba）或CASP8和fadd样细胞凋亡调节因子（Cflar）的表达没有差异。此外，我们发现包括Th、D1和D2受体在内的多巴胺能标记物以及包括GABA - a和谷氨酸脱羧酶2 （Gad2）在内的GABA信号标记物的mRNA表达水平在基因型之间没有差异。然而，我们发现谷氨酸脱羧酶1 （Gad1）在PD模型中显著降低，这表明PAG内的神经传递可能受到破坏。这些结果首次提出了一个假设，即该模型中的α -突触核蛋白聚集不是转录增加的结果，而是分解和清除的缺陷，并且观察到的声音缺陷可能与神经传递受损有关。总之，这些发现与假设一致，即神经底物敏感性的差异有助于PD的Pink1−/−大鼠模型的发声和交流动机的早期发病机制。我们的研究结果提出了新的治疗途径，包括溶酶体降解途径，可用于进一步研究声带功能障碍PD的发病机制和治疗。
Vocal communication deficits are common in Parkinson disease (PD). Widespread alpha-synuclein pathology is a common link between familial and sporadic PD, and recent genetic rat models based on familial genetic links increase the opportunity to explore vocalization deficits and their associated neuropathologies. Specifically, the Pink1 knockout (−/−) rat presents with early, progressive motor deficits, including significant vocal deficits, at 8 months of age. Moreover, this rat model exhibits alpha-synuclein pathology compared to age-matched non-affected wildtype (WT) controls. Aggregations are specifically dense within the periaqueductal gray (PAG), a brainstem region involved in the coordination of emotional and volitional control of vocalizations. Here, we investigated changes in gene expression within the PAG at 8 months of age in Pink1 −/− rats compared to WT. Our data demonstrate that Pink1 −/− rat mRNA expression levels of alpha-synuclein are comparable to WT. However, Pink1 −/− rats show significantly decreased levels of Atp13a2, a transmembrane lysosomal P5-type ATPase suggesting a potential mechanism for the observed abnormal aggregation. We found no difference in the expression of glucocerebrosidase (Gba) or the CASP8 and FADD-like apoptosis regulator (Cflar). Further, we show that mRNA expression levels of dopaminergic markers including Th, D1 and D2 receptor as well as GABA signaling markers including Gaba-A and glutamate decarboxylase 2 (Gad2) do not differ between genotypes. However, we found that glutamate decarboxylase 1 (Gad1) is significantly reduced in this PD model suggesting possible disruption of neurotransmission within the PAG. These results are the first to suggest the hypothesis that alpha-synuclein aggregation in this model is not a result of increased transcription, but rather a deficit in the breakdown and clearance, and that the observed vocal deficits may be related to impaired neural transmission. Altogether, these findings are consistent with the hypothesis that differences in neural substrate sensitivity contribute to the early pathogenesis of vocalizations and motivation to communicate in the Pink1 −/− rat model of PD. Our results suggest novel therapeutic pathways, including the lysosomal degradation pathway, which can be used in to further study the pathogenesis and treatment of vocal dysfunction PD.