S327 phosphorylation of the presynaptic protein SEPTIN5 increases in the early stages of neurofibrillary pathology and alters the functionality of SEPTIN5
S327 phosphorylation of the presynaptic protein SEPTIN5 increases in the early stages of neurofibrillary pathology and alters the functionality of SEPTIN5
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DOI：
10.1016/j.nbd.2021.105603
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发表时间：
2022-02-01
影响因子：
6.1
通讯作者：
Hiltunen，Mikko
中科院分区：
文献类型：
--
作者：
Ferreira，Catarina B.;Marttinen，Mikael;Hiltunen，Mikko
阿尔茨海默病(AD)是最常见的痴呆类型，其神经病理特征是细胞外含有淀粉样蛋白β的老年斑和细胞内由过度磷酸化的tau蛋白组成的神经原纤维缠结。以前的研究表明，Septin(Septin)蛋白家族成员在AD相关的细胞过程中发挥了作用。在这里，我们阐明了突触前SEPTIN5蛋白及其翻译后修饰在AD分子发病机制中的潜在作用。随着AD相关神经原纤维病变程度的加重，人类颞叶皮质中SEPTIN5的RNA和蛋白水平显著降低。相反，在AD相关神经纤维病理的早期阶段已经观察到功能相关的SEPTIN5磷酸化位点S327的磷酸化增加，但在符合AD轻度认知损害标准的个体的脑脊液中并未观察到。根据机制评估，在慢病毒构建的编码SEPTIN5或SEPTIN5野生型磷酸化突变体(S327A和S327D)的原代小鼠皮质神经元中，发现了SEPTIN5 S327磷酸化状态与SEPTIN5对淀粉样前体蛋白加工和自噬标记的影响之间的联系。海马区注射慢病毒野生型SEPTIN5或磷酸化突变结构的C57BL/6-J小鼠在注射开始五到六周后没有表现出认知能力的变化。然而，SEPTIN5 S327的磷酸化状态与CA3-CA1突触的短期突触可塑性的变化有关。总之，这些数据表明，SEPTIN5及其S327磷酸化状态在与AD相关的几个细胞过程中发挥着关键作用。
Alzheimer's disease (AD) is the most common form of dementia, which is neuropathologically characterized by extracellular senile plaques containing amyloid-β and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. Previous studies have suggested a role for septin (SEPTIN) protein family members in AD-associated cellular processes. Here, we elucidated the potential role of presynaptic SEPTIN5 protein and its post-translational modifications in the molecular pathogenesis of AD. RNA and protein levels of SEPTIN5 showed a significant decrease in human temporal cortex in relation to the increasing degree of AD-related neurofibrillary pathology. Conversely, an increase in the phosphorylation of the functionally relevant SEPTIN5 phosphorylation site S327 was observed already in the early phases of AD-related neurofibrillary pathology, but not in the cerebrospinal fluid of individuals fulfilling the criteria for mild cognitive impairment due to AD. According to the mechanistic assessments, a link between SEPTIN5 S327 phosphorylation status and the effects of SEPTIN5 on amyloid precursor protein processing and markers of autophagy was discovered in mouse primary cortical neurons transduced with lentiviral constructs encoding wild type SEPTIN5 or SEPTIN5 phosphomutants (S327A and S327D). C57BL/6 J mice intrahippocampally injected with lentiviral wild type SEPTIN5 or phosphomutant constructs did not show changes in cognitive performance after five to six weeks from the start of injections. However, SEPTIN5 S327 phosphorylation status was linked to changes in short-term synaptic plasticityex vivoat the CA3-CA1 synapse. Collectively, these data suggest that SEPTIN5 and its S327 phosphorylation status play a pivotal role in several cellular processes relevant for AD.