PDF(Pubmed)
Abstract：
Parkinson\'s disease (PD) is characterized not only by motor symptoms but also by non-motor dysfunctions, such as olfactory impairment; the cause is not fully understood. Our study suggests that neuronal loss and inflammation in brain regions along the olfactory pathway, such as the olfactory bulb (OB) and the piriform cortex (PC), may contribute to olfactory dysfunction in PD mice, which might be related to the downregulation of the trace amine-associated receptor 1 (TAAR1) in these areas. In the striatum, although only a decrease in mRNA level, but not in protein level, of TAAR1 was detected, bioinformatic analyses substantiated its correlation with PD. Moreover, we discovered that neuronal death and inflammation in the OB and the PC in PD mice might be regulated by TAAR through the Bcl-2/caspase3 pathway. This manifested as a decrease of anti-apoptotic protein Bcl-2 and an increase of the pro-apoptotic protein cleaved caspase3, or through regulating astrocytes activity, manifested as the increase of TAAR1 in astrocytes, which might lead to the decreased clearance of glutamate and consequent neurotoxicity. In summary, we have identified a possible mechanism to elucidate the olfactory dysfunction in PD, positing neuronal damage and inflammation due to apoptosis and astrocyte activity along the olfactory pathway in conjunction with the downregulation of TAAR1.
摘要：
帕金森病（PD）的特征不仅是运动症状，而且是非运动功能障碍，如嗅觉受损；原因还不完全清楚。我们的研究表明，沿着嗅觉通路的大脑区域的神经元丢失和炎症，如嗅球(OB)和梨状皮层(PC)，可能导致PD小鼠的嗅觉功能障碍，这可能与这些区域的痕量胺相关受体1（TAAR1）的下调有关。在纹状体，虽然只是mRNA水平的下降，但不是在蛋白质水平，检测到TAAR1，生物信息学分析证实了其与PD的相关性。此外，我们发现，PD小鼠OB和PC的神经元死亡和炎症可能受TAAR通过Bcl-2/caspase3通路调节。这表现为抗凋亡蛋白Bcl-2的减少和促凋亡蛋白裂解的caspase3的增加，或通过调节星形胶质细胞活性，表现为星形胶质细胞中TAAR1的增加，这可能会导致谷氨酸的清除率降低，从而导致神经毒性。总之,我们已经确定了一种可能的机制来阐明PD的嗅觉功能障碍，定位神经元损伤和炎症由于细胞凋亡和星形胶质细胞活性沿着嗅觉途径结合下调TAAR1。
