A neurodegeneration gene, WDR45, links impaired ferritinophagy to iron accumulation.
A neurodegeneration gene, WDR45, links impaired ferritinophagy to iron accumulation.
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DOI：
10.1111/jnc.15548
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发表时间：
2022-03
影响因子：
4.7
通讯作者：
Seo YA
中科院分区：
文献类型：
--
作者：
Aring L;Choi EK;Kopera H;Lanigan T;Iwase S;Klionsky DJ;Seo YA
神经变性伴脑铁积累（NBIA）是一种临床和遗传异质性的神经退行性疾病，其特征是脑铁的异常积累和神经系统的进行性变性。最近发现的NBIA亚型之一是β -螺旋桨蛋白相关神经变性（BPAN）。BPAN是由WDR45/WIPI4 （WD重复结构域45）基因的新生突变引起的。WDR45是酵母Atg18的四种哺乳动物同源物之一，Atg18是一种自噬调节因子。BPAN患者和动物模型的WDR45缺乏可能导致自噬通量的缺陷。然而，WDR45缺乏如何导致脑铁超载仍不清楚。为了阐明WDR45的作用，我们使用CRISPR - Cas9介导的基因组编辑技术生成了一个WDR45敲除（KO） SH - SY5Y神经母细胞瘤细胞系。利用这些细胞，我们证明了非转铁蛋白结合的铁途径主要介导铁的积累。此外，WDR45的缺失导致铁蛋白自噬缺陷，铁蛋白自噬是一种降解铁蛋白储存的自噬形式。我们发现，受损的铁蛋白自噬有助于WDR45‐KO细胞中的铁积累。在线粒体中也检测到铁积累，这伴随着线粒体呼吸受损、活性氧升高和细胞死亡增加。因此，我们的研究将WDR45与特定的铁获取途径和铁蛋白自噬联系起来。本期封面图片：https://doi.org/10.1111/jnc.15388 WDR45缺乏对铁积累、铁蛋白吞噬和细胞死亡影响的示意图模型。WDR45缺失细胞通过非转铁蛋白结合铁途径（NTBI）积累铁。总铁水平的升高伴随着铁储存蛋白铁蛋白的升高。WDR45缺乏损害铁蛋白自噬，即铁蛋白的自噬降解。在线粒体中也检测到铁水平升高，这可能损害线粒体功能，提高活性氧，增加细胞死亡。本期封面图片：https://doi.org/10.1111/jnc.15388
Neurodegeneration with brain iron accumulation (NBIA) is a clinically and genetically heterogeneous group of neurodegenerative diseases characterized by the abnormal accumulation of brain iron and the progressive degeneration of the nervous system. One of the recently identified subtypes of NBIA is β‐propeller protein‐associated neurodegeneration (BPAN). BPAN is caused by de novo mutations in the WDR45/WIPI4 (WD repeat domain 45) gene. WDR45 is one of the four mammalian homologs of yeast Atg18, a regulator of autophagy. WDR45 deficiency in BPAN patients and animal models may result in defects in autophagic flux. However, how WDR45 deficiency leads to brain iron overload remains unclear. To elucidate the role of WDR45, we generated a WDR45‐knockout (KO) SH‐SY5Y neuroblastoma cell line using CRISPR‐Cas9‐mediated genome editing. Using these cells, we demonstrated that the non‐TF (transferrin)‐bound iron pathway dominantly mediated the accumulation of iron. Moreover, the loss of WDR45 led to defects in ferritinophagy, a form of autophagy that degrades the iron storage protein ferritin. We showed that impaired ferritinophagy contributes to iron accumulation in WDR45‐KO cells. Iron accumulation was also detected in the mitochondria, which was accompanied by impaired mitochondrial respiration, elevated reactive oxygen species, and increased cell death. Thus, our study links WDR45 to specific iron acquisition pathways and ferritinophagy. Cover Image for this issue: https://doi.org/10.1111/jnc.15388 Schematic model for impact of WDR45 deficiency on iron accumulation, ferritinophagy, and cell death. WDR45‐deficient cells accumulate iron via the nontransferrin‐bound iron pathway (NTBI). The increased total iron levels were accompanied by an increase of the iron storage protein ferritin. WDR45 deficiency impairs ferritinophagy, the autophagic degradation of ferritin. Elevated iron levels were also detected in the mitochondria, which may impair mitochondrial function, elevate reactive oxygen species, and increase cell death. Cover Image for this issue: https://doi.org/10.1111/jnc.15388
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影响因子：
64.5
作者：
Duce JA;Tsatsanis A;Cater MA;James SA;Robb E;Wikhe K;Leong SL;Perez K;Johanssen T;Greenough MA;Cho HH;Galatis D;Moir RD;Masters CL;McLean C;Tanzi RE;Cappai R;Barnham KJ;Ciccotosto GD;Rogers JT;Bush AI
通讯作者：
Bush AI
影响因子：
5
作者：
Arber CE;Li A;Houlden H;Wray S
通讯作者：
Wray S
影响因子：
5
作者：
Kimura, Noriyuki;Kumamoto, Toshihide;Arakawa, Ryuki
通讯作者：
Arakawa, Ryuki
影响因子：
9.8
作者：
Haack, Tobias B.;Hogarth, Penelope;Hayflick, Susan J.
通讯作者：
Hayflick, Susan J.
影响因子：
4.8
作者：
Abboud, S;Haile, DJ
通讯作者：
Haile, DJ