Linking Gba1 E326K mutation to microglia activation and mild age-dependent dopaminergic Neurodegeneration.
Linking Gba1 E326K mutation to microglia activation and mild age-dependent dopaminergic Neurodegeneration.
复制标题
将 Gba1 E326K 突变与小胶质细胞激活和轻度年龄依赖性多巴胺能神经变性联系起来。
DOI：
10.1101/2023.09.14.557673
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Ko,HanSeok
中科院分区：
文献类型：
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作者：
Kweon,SinHo;Ryu,HyeGuk;Park,Hyeonwoo;Lee,Saebom;Kim,Namshik;Kwon,Seung-Hwan;Ma,Shi-Xun;Kim,Sangjune;Ko,HanSeok
GBA 1基因突变已被确定为帕金森病（PD）的一个普遍遗传风险因素。GBA 1突变损害酶活性，导致溶酶体功能障碍和α-突触核蛋白（α-syn）水平升高。虽然大多数研究主要集中在GBA 1在促进突触核蛋白病中的作用，但新出现的证据表明，神经炎症可能是GBA 1缺乏引起的关键致病性改变。为了研究GBA 1缺陷介导的神经炎症的分子机制，我们使用CRISPR/Cas9技术产生了Gba 1 E326 K敲入（KI）小鼠，这与PD和路易体痴呆（DLB）的风险增加有关。在24个月大的Gba 1 E326 K KI小鼠的腹侧中脑和海马中，我们发现GBA 1酶活性中度下降，葡萄糖神经酰胺积聚，小胶质细胞密度增加。此外，我们观察到在用病理性α-syn预形成纤维（PFF）处理后，分别在从Gba 1 E326 K KI小鼠培养的原代小胶质细胞和星形胶质细胞中促炎细胞因子水平增加和反应性星形胶质细胞形成。此外，在Gba 1 E326 K KI小鼠中肠道接种α-syn PFF显著增强了海马齿状回中路易体的蓄积，并伴有神经炎症加重和非运动症状加重。这项研究显著增强了我们对Gba 1 E326 K突变参与神经炎症和大脑中致病性α-syn的细胞间传递的理解，从而开辟了新的治疗途径。
Mutations in the GBA1 gene have been identified as a prevalent genetic risk factor for Parkinson’s disease (PD). GBA1 mutations impair enzymatic activity, leading to lysosomal dysfunction and elevated levels of α-synuclein (α-syn). While most research has primarily focused on GBA1’s role in promoting synucleinopathy, emerging evidence suggests that neuroinflammation may be a key pathogenic alteration caused by GBA1 deficiency. To examine the molecular mechanism underlying GBA1 deficiency-mediated neuroinflammation, we generated Gba1 E326K knock-in (KI) mice using the CRISPR/Cas9 technology, which is linked to an increased risk of PD and dementia with Lewy bodies (DLB). In the ventral midbrain and hippocampus of 24-month-old Gba1 E326K KI mice, we found a moderate decline in GBA1 enzymatic activity, a buildup of glucosylceramide, and an increase in microglia density. Furthermore, we observed increased levels of pro-inflammatory cytokines and formation of reactive astrocytes in primary microglia and astrocytes, respectively, cultured from Gba1 E326K KI mice following treatment with pathologic α-syn preformed fibrils (PFF). Additionally, the gut inoculation of α-syn PFF in Gba1 E326K KI mice significantly enhanced the accumulation of Lewy bodies in the dentate gyrus of the hippocampus, accompanied by aggravated neuroinflammation and exacerbated non-motor symptoms. This research significantly enhances our understanding of the Gba1 E326K mutation’s involvement in neuroinflammation and the cell-to-cell transmission of pathogenic α-syn in the brain, thereby opening new therapeutic avenues.