Mitochondrial genome mutations and neuronal dysfunction of induced pluripotent stem cells derived from patients with Alzheimer's disease.
Mitochondrial genome mutations and neuronal dysfunction of induced pluripotent stem cells derived from patients with Alzheimer's disease.
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阿尔茨海默病患者诱导多能干细胞的线粒体基因组突变和神经元功能障碍
DOI：
10.1111/cpr.13274
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发表时间：
2022-07
影响因子：
8.5
通讯作者：
中科院分区：
文献类型：
--
作者：
患者来源的诱导多能干细胞（iPSC）是可用于自体干细胞治疗的材料。我们筛选了阿尔茨海默病 (AD) 患者的 iPSC 和 iPSC 衍生神经元细胞中的 mtDNA 突变。此外，我们还研究了这些突变是否会影响分化神经元细胞中的线粒体功能和 β-淀粉样蛋白 (Aβ) 的沉积。测量并比较了 iPSC 和 iPSC 衍生神经元细胞的 mtDNA 突变。对选定的携带 mtDNA 突变的 iPSC 进行亚克隆，然后分析其生长速度和神经元分化模式。测量分化细胞的线粒体呼吸和膜电位以及 Aβ 沉积。大多数来自AD受试者的iPSC都含有≥1个mtDNA突变，并且突变数量明显高于脐带血中的iPSC。 iPSC 中约 35% 和 40% 的突变分别与同基因 iPSC 及其分化的神经元前体细胞共享，具有相似或不同的异质性。此外，克隆 iPSC 的突变在扩展培养和神经元分化过程中保持稳定。最后，mtDNA 突变可以诱导生长优势，包括更高的活力和增殖、更低的线粒体呼吸和膜电位以及增加的 Aβ 沉积。这项研究表明，AD 患者的 mtDNA 突变可能导致线粒体功能障碍并加速 Aβ 沉积。因此，早期筛查 iPSC 系中的 mtDNA 突变对于开发 AD 患者的自体细胞疗法或药物筛选至关重要。在源自阿尔茨海默病患者的诱导多能干细胞中发现了 mtDNA 突变。由于其高活力和增殖能力，这些突变可以诱导生长优势。具有 mtDNA 突变的分化神经元细胞表现出线粒体和神经元功能障碍，以及 Aβ 沉积增加。
Patient‐derived induced pluripotent stem cells (iPSCs) are materials that can be used for autologous stem cell therapy. We screened mtDNA mutations in iPSCs and iPSC‐derived neuronal cells from patients with Alzheimer's disease (AD). Also, we investigated whether the mutations could affect mitochondrial function and deposition of β‐amyloid (Aβ) in differentiated neuronal cells. mtDNA mutations were measured and compared among iPSCs and iPSC‐derived neuronal cells. The selected iPSCs carrying mtDNA mutations were subcloned, and then their growth rate and neuronal differentiation pattern were analyzed. The differentiated cells were measured for mitochondrial respiration and membrane potential, as well as deposition of Aβ. Most iPSCs from subjects with AD harbored ≥1 mtDNA mutations, and the number of mutations was significantly higher than that from umbilical cord blood. About 35% and 40% of mutations in iPSCs were shared with isogenic iPSCs and their differentiated neuronal precursor cells, respectively, with similar or different heteroplasmy. Furthermore, the mutations in clonal iPSCs were stable during extended culture and neuronal differentiation. Finally, mtDNA mutations could induce a growth advantage with higher viability and proliferation, lower mitochondrial respiration and membrane potential, as well as increased Aβ deposition. This study demonstrates that mtDNA mutations in patients with AD could lead to mitochondrial dysfunction and accelerated Aβ deposition. Therefore, early screening for mtDNA mutations in iPSC lines would be essential for developing autologous cell therapy or drug screening for patients with AD. mtDNA mutations were found in induced pluripotent stem cells derived from patients with Alzheimer's disease. The mutations could induce growth advantage due to their high viability and proliferation. Differentiated neuronal cells with mtDNA mutations exhibited mitochondrial and neuronal dysfunction, as well as increased Aβ deposition.
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DOI：
10.1016/j.beem.2012.05.003
发表时间：
2012-12
期刊：
Best practice & research. Clinical endocrinology & metabolism
影响因子：
--
作者：
Osellame LD;Blacker TS;Duchen MR
通讯作者：
Duchen MR
影响因子：
46.9
作者：
通讯作者：
--
影响因子：
--
作者：
Jazvinšćak Jembrek M;Hof PR;Šimić G
通讯作者：
Šimić G
影响因子：
0.8
作者：
Sivandzade, Farzane;Bhalerao, Aditya;Cucullo, Luca
通讯作者：
Cucullo, Luca
DOI：
10.1016/j.bbamcr.2019.02.010
发表时间：
2019-05-01
影响因子：
5.1
作者：
Villanueva-Paz, Marina;Povea-Cabello, Suleva;Sanchez-Alcazar, Jose A.
通讯作者：
Sanchez-Alcazar, Jose A.