Sex-Specific Microglial Responses to Glucocerebrosidase Inhibition: Relevance to GBA1-Linked Parkinson's Disease.
Sex-Specific Microglial Responses to Glucocerebrosidase Inhibition: Relevance to GBA1-Linked Parkinson's Disease.
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作者：
小胶质细胞是一种异质细胞，具有不同的群体特征，每个群体都对神经系统中的特定生物学过程做出贡献，包括神经保护。为了阐明性别特异性小胶质细胞的异质性对神经元应激敏感性的影响，我们用延时显微镜录像记录了来自两性小鼠的原代细胞在促炎或神经毒性刺激下发生的形状和运动的变化。通过这种形态功能分析，我们记录了不同的小胶质细胞亚群对刺激的性别特异性反应：男性小胶质细胞倾向于具有更多的促炎表型，而女性小胶质细胞对糖脑苷酶的小分子抑制物康力醇-B-环氧化物(CBE)表现出更高的敏感性，该酶由GBA1基因编码，其突变是帕金森病(PD)的主要风险因素。有趣的是，葡萄糖脑苷酶的抑制尤其削弱了女性小胶质细胞增强神经元中Nrf2依赖的解毒途径的能力，削弱了这种神经保护功能中观察到的性别差异。这一发现与GBA1突变的临床影响是一致的，其中在女性个体中观察到的发展为特发性帕金森病风险降低1.5-2倍的风险在GBA1携带者人群中缺失，从而表明小胶质细胞在PD-GBA1的发病机制中具有性别特异性作用。
Microglia are heterogenous cells characterized by distinct populations each contributing to specific biological processes in the nervous system, including neuroprotection. To elucidate the impact of sex-specific microglia heterogenicity to the susceptibility of neuronal stress, we video-recorded with time-lapse microscopy the changes in shape and motility occurring in primary cells derived from mice of both sexes in response to pro-inflammatory or neurotoxic stimulations. With this morpho-functional analysis, we documented distinct microglia subpopulations eliciting sex-specific responses to stimulation: male microglia tended to have a more pro-inflammatory phenotype, while female microglia showed increased sensitivity to conduritol-B-epoxide (CBE), a small molecule inhibitor of glucocerebrosidase, the enzyme encoded by the GBA1 gene, mutations of which are the major risk factor for Parkinson’s Disease (PD). Interestingly, glucocerebrosidase inhibition particularly impaired the ability of female microglia to enhance the Nrf2-dependent detoxification pathway in neurons, attenuating the sex differences observed in this neuroprotective function. This finding is consistent with the clinical impact of GBA1 mutations, in which the 1.5–2-fold reduced risk of developing idiopathic PD observed in female individuals is lost in the GBA1 carrier population, thus suggesting a sex-specific role for microglia in the etiopathogenesis of PD-GBA1.
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DOI：
10.1007/978-1-62703-520-0_27
发表时间：
2013
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Garcia, Jenny A;Cardona, Sandra M;Cardona, Astrid E
通讯作者：
Cardona, Astrid E
影响因子：
56.9
作者：
BEUTLER, E
通讯作者：
BEUTLER, E
影响因子：
8.8
作者：
Guneykaya, Dilansu;Ivanov, Andranik;Wolf, Susanne A.
通讯作者：
Wolf, Susanne A.
影响因子：
6.2
作者：
Hanamsagar R;Alter MD;Block CS;Sullivan H;Bolton JL;Bilbo SD
通讯作者：
Bilbo SD
影响因子：
9.3
作者：
Han J;Fan Y;Zhou K;Blomgren K;Harris RA
通讯作者：
Harris RA