Heterozygous GBA D409V and ATP13a2 mutations do not exacerbate pathological α-synuclein spread in the prodromal preformed fibrils model in young mice
Heterozygous GBA D409V and ATP13a2 mutations do not exacerbate pathological α-synuclein spread in the prodromal preformed fibrils model in young mice
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DOI：
10.1016/j.nbd.2021.105513
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发表时间：
2021-09-21
影响因子：
6.1
通讯作者：
Brundin, Patrik
中科院分区：
文献类型：
--
作者：
Johnson, Michaela E.;Bergkvist, Liza;Brundin, Patrik
自噬失调和溶酶体损伤与帕金森病的发病机制有关，部分原因是在这些途径中涉及多个基因的突变，如GBA、SNCA、ATP13a2（也称为PARK9）、TMEM175和LRRK2。导致溶酶体功能障碍的突变通过增加α -突触核蛋白水平而导致帕金森病，而α -突触核蛋白水平反过来又可能促进该蛋白的聚集。在这里，我们使用了两种不同的遗传模型——一种杂合的GBA蛋白突变形式（D409V），另一种杂合的ATP13a2功能缺失突变，来测试这些突变是否会在12周龄小鼠嗅球注射α -突触核蛋白预形成原纤维后加剧α -突触核蛋白病理的传播。与我们的假设相反，我们发现，与野生型小鼠相比，携带GBA D409（+/-）和ATP13a2（+/-）突变的小鼠没有加重行为障碍或组织病理学（a-synuclein， LAMP2和Iba1）。这表明，在幼鼠大脑中，GBA D409V突变或ATP13a2功能丧失突变都不会加速a-突触核蛋白病理的传播。因此，我们假设这些突变仅通过在帕金森氏病致病过程的一个初始上游事件中起作用而增加帕金森氏病的风险。此外，一旦致病过程被触发，突变及其影响的分子途径似乎发挥的作用就不那么重要了，因此不会特异性地影响α -突触核蛋白的病理传播。
Autophagic dysregulation and lysosomal impairment have been implicated in the pathogenesis of Parkinson's disease, partly due to the identification of mutations in multiple genes involved in these pathways such as GBA, SNCA, ATP13a2 (also known as PARK9), TMEM175 and LRRK2. Mutations resulting in lysosomal dysfunction are proposed to contribute to Parkinson's disease by increasing alpha-synuclein levels, that in turn may promote aggregation of this protein. Here, we used two different genetic models-one heterozygous for a mutated form of the GBA protein (D409V), and the other heterozygous for an ATP13a2 loss-of-function mutation, to test whether these mutations exacerbate the spread of alpha-synuclein pathology following injection of alpha-synuclein preformed fibrils in the olfactory bulb of 12-week-old mice. Contrary to our hypothesis, we found that mice harboring GBA D409(+/-) and ATP13a2(+/-) mutations did not have exacerbated behavioral impairments or histopathology (a-synuclein, LAMP2, and Iba1) when compared to their wildtype littermates. This indicates that in the young mouse brain, neither the GBA D409V mutation or ATP13a2 loss-of-function mutation accelerate the spread of a-synuclein pathology. As a consequence, we postulate that these mutations increase Parkinson's disease risk only by acting in one of the initial, upstream events in the Parkinson's disease pathogenic process. Further, the mutations, and the molecular pathways they impact, appear to play a less important role once the pathogenic process has been triggered and therefore do not specifically influence alpha-synuclein pathology spread.