Golgi damage caused by dysfunction of PiT-2 in primary familial brain calcification.
Golgi damage caused by dysfunction of PiT-2 in primary familial brain calcification.
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DOI：
10.1016/j.bbrc.2022.12.050
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发表时间：
2022-12
影响因子：
3.1
通讯作者：
Huifang Sun;Zhuoya Wang;Qi Zhang;Na Chen;Mi-bo Tang;Zhihua Yang;Yan-lin Wang;Jiansheng Kang-Jiansheng-Kan
中科院分区：
文献类型：
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作者：
Huifang Sun;Zhuoya Wang;Qi Zhang;Na Chen;Mi-bo Tang;Zhihua Yang;Yan-lin Wang;Jiansheng Kang-Jiansheng-Kan
高尔基体对于蛋白质修饰和分子运输至关重要。它对于神经发育和活动是必不可少的，并且其损伤涉及许多神经系统疾病。原发性家族性脑钙化（PFBC）是一种以多发性脑钙化为特征的遗传性神经退行性疾病，SLC 20 A2是PFBC的主要致病基因，编码无机磷酸盐转运蛋白2（PiT-2）。PiT-2蛋白是钠依赖性磷酸盐III型转运蛋白，功能障碍导致无机磷酸盐（Pi）和钙沉积的细胞摄入不足。受损的高尔基体是否参与PFBC的进程需要阐明。本研究从2例SLC 20 A2基因突变（c.613G > Aordel exon 10）的PFBC患者和2例健康志愿者中分离出诱导性多能干细胞（induced pluripotent stem cells，iPSCs），作为研究PFBC发病机制的可靠细胞模型。为了研究其机制，我们在体外将iPSCs分化为神经元和星形胶质细胞。我们的研究发现PFBC神经元中高尔基体结构破坏和自噬受损，mTOR活性增加。我们还发现PFBC多巴胺能神经元和星形胶质细胞的线粒体受损和凋亡增加。在这项研究中，我们证明了功能失调的PiT-2导致细胞Pi的不平衡，这可能会破坏高尔基体，导致PFBC中的自噬、线粒体和凋亡受损。本研究为认识脑钙化的神经损害和致病机制提供了新的途径。
The Golgi apparatus is vital for protein modification and molecular trafficking. It is essential for nerve development and activity, and damage thereof is implicated in many neurological diseases. Primary familial brain calcification (PFBC) is a rare inherited neurodegenerative disease characterized by multiple brain calcifications.SLC20A2, which encodes the inorganic phosphate transporter 2 (PiT-2) protein, is the main pathogenic gene in PFBC. The PiT-2 protein is a sodium-dependent phosphate type III transporter, and dysfunction leads to a deficit in the cellular intake of inorganic phosphate (Pi) and calcium deposits. Whether the impaired Golgi apparatus is involved in the PFBC procession requires elucidation. In this study, we constructed induced pluripotent stem cells (iPSCs) derived from two PFBC patients with differentSLC20A2gene mutations (c.613G > Aordel exon10) and two healthy volunteers as dependable cell models for research on pathogenic mechanism. To study the mechanism, we differentiated iPSCs into neurons and astrocytes in vitro. Our study found disruptive Golgi structure and damaged autophagy in PFBC neurons with increased activity of mTOR. We also found damaged mitochondria and increased apoptosis in the PFBC dopaminergic neurons and astrocytes. In this study, we prove that dysfunctional PiT-2 leads to an imbalance of cellular Pi, which may disrupt the Golgi apparatus with impaired autophagy, mitochondria and apoptosis in PFBC. Our study provides a new avenue for understanding nerve damage and pathogenic mechanism in brain calcifications.