Protein mishandling and impaired lysosomal proteolysis generated through calcium dysregulation in Alzheimer's disease.
Protein mishandling and impaired lysosomal proteolysis generated through calcium dysregulation in Alzheimer's disease.
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在阿尔茨海默病中，由于钙调节失调而产生的蛋白质处理不当和溶酶体蛋白分解受损。
DOI：
10.1073/pnas.2211999119
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发表时间：
2022-12-06
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
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作者：
我们在模型细胞、鼠神经元培养物和iPSC衍生的人神经元中证明，AD相关的RyR-Ca 2+稳态异常损害溶酶体酸化、溶酶体蛋白水解活性并阻碍自噬介导的蛋白聚集体清除，这是对神经元存活至关重要的过程。这些赤字逆转恢复细胞内Ca 2+稳态。值得注意的是，这提供了一个治疗靶点，并强调了已知在AD中改变的ER-Ca 2+处理与作为阿尔茨海默病早期关键转折点的致病性蛋白质积累之间的致病性关系。神经溶酶体和自噬介导的细胞碎片降解的损伤导致神经炎性营养不良和突触丢失。虽然这些是神经退行性疾病如阿尔茨海默病（AD）的充分表征的特征，但是驱动致病蛋白质错误处理的缺陷的上游细胞过程较少被理解。使用一系列的荧光生物传感器和光学成像在模型细胞，AD小鼠模型和人类神经元来自AD患者，我们揭示了一个以前未描述的细胞信号级联相关的蛋白质处理不当介导的细胞内钙离子失调，早期组件AD发病机制。通过内质网（ER）驻留的兰尼碱受体（RyR）释放的Ca 2+增加与溶酶体质子泵液泡-ATP酶（vATP酶）亚基（V1 B2和V0 a1）表达减少相关，导致AD小鼠模型和人诱导神经元（HiN）中溶酶体脱酸和蛋白水解活性破坏。由于溶酶体消化能力受损，具有过度磷酸化tau的成熟自噬体在AD鼠神经元和AD HiN中积累，从而加剧蛋白质病。用负变构调节剂丹曲林（Ryanodex）使AD相关异常RyR-Ca 2+信号正常化，恢复了AD神经元中的vATP酶水平、溶酶体酸化和蛋白水解活性以及细胞内蛋白聚集体的自噬清除。这些结果突出表明，在明显的AD组织病理学或认知缺陷之前，异常的上游Ca 2+信号传导破坏溶酶体酸化，并有助于细胞内蛋白质聚集体的病理学积累。重要的是，这在AD的动物模型和来自AD患者的人iPSC衍生的神经元中得到证实。此外，RyR-Ca 2+释放的药理学抑制挽救了蛋白水解功能，揭示了治疗干预的靶点，该靶点已在临床相关测定中显示出效果。
We demonstrate in model cells, murine neuronal cultures, and iPSC-derived human neurons, that AD-associated RyR-Ca2+ dyshomeostasis impairs lysosomal acidification, lysosomal proteolytic activity and hinders autophagic-mediated protein aggregate clearance, which are processes vital to neuronal survival. These deficits were reversed by restoring intracellular Ca2+ homeostasis. Notably, this provides a therapeutic target and emphasizes the pathogenic relationship between ER-Ca2+ handling, that is known to be altered in AD, and pathogenic protein accumulation as a critical turning point in early stages of Alzheimer’s disease. Impairments in neural lysosomal- and autophagic-mediated degradation of cellular debris contribute to neuritic dystrophy and synaptic loss. While these are well-characterized features of neurodegenerative disorders such as Alzheimer’s disease (AD), the upstream cellular processes driving deficits in pathogenic protein mishandling are less understood. Using a series of fluorescent biosensors and optical imaging in model cells, AD mouse models and human neurons derived from AD patients, we reveal a previously undescribed cellular signaling cascade underlying protein mishandling mediated by intracellular calcium dysregulation, an early component of AD pathogenesis. Increased Ca2+ release via the endoplasmic reticulum (ER)-resident ryanodine receptor (RyR) is associated with reduced expression of the lysosome proton pump vacuolar-ATPase (vATPase) subunits (V1B2 and V0a1), resulting in lysosome deacidification and disrupted proteolytic activity in AD mouse models and human-induced neurons (HiN). As a result of impaired lysosome digestive capacity, mature autophagosomes with hyperphosphorylated tau accumulated in AD murine neurons and AD HiN, exacerbating proteinopathy. Normalizing AD-associated aberrant RyR-Ca2+ signaling with the negative allosteric modulator, dantrolene (Ryanodex), restored vATPase levels, lysosomal acidification and proteolytic activity, and autophagic clearance of intracellular protein aggregates in AD neurons. These results highlight that prior to overt AD histopathology or cognitive deficits, aberrant upstream Ca2+ signaling disrupts lysosomal acidification and contributes to pathological accumulation of intracellular protein aggregates. Importantly, this is demonstrated in animal models of AD, and in human iPSC-derived neurons from AD patients. Furthermore, pharmacological suppression of RyR-Ca2+ release rescued proteolytic function, revealing a target for therapeutic intervention that has demonstrated effects in clinically-relevant assays.
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影响因子：
5.3
作者：
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影响因子：
3.7
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DOI：
10.1083/jcb.201412046
发表时间：
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期刊：
The Journal of cell biology
影响因子：
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Sheng ZH