嗅球α-突触核蛋白沉积在帕金森病嗅觉减退中的作用及机制研究

Hyposmia, as one of the most common non-motor symptoms(NMS) , plays an important role in the early and differential diagnosis of Parkinson’s disease(PD). Accumulating evidence in recent years indicated that it was related to α-synuclein accumulation in central olfactory regions, especially in olfactory bulb. Unfortunately the underlying mechanism was poorly understood. Our pilot clinical observational study found olfactory identification score of PD patients was associated with genotypic distribution of rs11931074, one SNP located in SNCA 3’UTR, indicating SNCA variant may contribute to the development of hyposmia in PD via influencing α-synuclein expression. As an important relay region of olfactory information, olfactory bulb also receives centrifugal cholinergic innervations, which regulate the olfactory synaptic transmission and local neuroinflammation. The present project aims to investigate the impact of α-synuclein accumulation to cholinergic denervation and neuroinflammation in olfactory bulb and olfactory behavior by in vivo and in vitro experiments, in addition to further validation the association of olfactory phenotype and genotype of two SNCA SNPs in PD patients, which may provide valuable clues about the molecular mechanism of hyposmia in PD.

作为帕金森病(PD)常见的非运动症状之一，嗅觉减退在PD早期诊断及鉴别诊断中具有重要作用,其发生可能与α-synuclein在嗅球等中枢嗅区的沉积有关，但具体机制不清。我们前期工作发现，位于α-synuclein基因 SNCA 3’UTR的SNP rs11931074与患者嗅棒气味识别能力得分有关，提示SNCA基因变异可能通过影响体内α-synuclein的表达水平从而参与PD嗅觉减退的发生。作为嗅觉信息传递的重要中继站，嗅球也接受来自基底前脑胆碱能纤维传递，从而调控嗅觉信息传递及局部炎症反应。为探讨PD嗅觉减退的潜在病理生理过程，我们希望在进一步临床大样本病例嗅觉表型-基因型验证的基础上，通过体内外实验明确α-synuclein沉积对嗅球胆碱能失神经支配、神经炎症的影响及与嗅觉行为的相关性。项目的开展将为揭示PD嗅觉减退的分子机制及寻找潜在的早期诊断标志物提供有价值的新线索和基础依据。

作为帕金森病(PD)常见的非运动症状之一，嗅觉减退在PD的早期诊断及鉴别诊断中具有重要参考价值, 其发生可能与α-synuclein在嗅球等中枢相关嗅觉区域的沉积有关，但具体机制不清。我们的临床表型-基因型研究发现，伴有嗅觉减退的PD患者呈现高龄、快眼动睡眠行为障碍（RBD）及便秘发生率增高的特点，此外还与SNCA rs11931074基因型分布有关。与GG型相比，rs11931074 TT基因型会增加患者嗅觉减退(OR =3.24)的发生率。进一步的功能实验发现后，rs11931074中T等位基因与患者唾液总α-synuclein的高水平有关，提示rs11931074基因型可能通过调节人体α-synuclein的表达，进而影响患者的嗅觉表型。动物行为学研究发现，A53T-α-synuclein 转基因小鼠在运动功能改变之前就存在嗅觉功能障碍。A53T-α-synuclein 转基因小鼠自6月起，比野生型要花更多的时间才能找到食物颗粒，提示动物存在嗅觉阈值下降，而此时黒质多巴胺能神经元尚无明显变化，动物尚无运动功能改变。免疫荧光结果显示，6月起嗅球小胶质细胞数增多，9月起嗅球中僧帽细胞层乙酰胆碱转移酶（ChAT）阳性的细胞数目明显减少，研究结果为揭示PD嗅觉减退的相关因素及分子机制提供了有价值的新证据和基础依据。