Aberrant upregulation of the glycolytic enzyme PFKFB3 in CLN7 neuronal ceroid lipofuscinosis.
Aberrant upregulation of the glycolytic enzyme PFKFB3 in CLN7 neuronal ceroid lipofuscinosis.
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DOI：
10.1038/s41467-022-28191-1
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发表时间：
2022-01-27
影响因子：
16.6
通讯作者：
Bolaños JP
中科院分区：
文献类型：
--
作者：
Lopez-Fabuel I;Garcia-Macia M;Buondelmonte C;Burmistrova O;Bonora N;Alonso-Batan P;Morant-Ferrando B;Vicente-Gutierrez C;Jimenez-Blasco D;Quintana-Cabrera R;Fernandez E;Llop J;Ramos-Cabrer P;Sharaireh A;Guevara-Ferrer M;Fitzpatrick L;Thompton CD;McKay TR;Storch S;Medina DL;Mole SE;Fedichev PO;Almeida A;Bolaños JP
CLN 7神经元蜡样脂褐质沉积症是一种在儿童中高度流行的遗传性溶酶体储存神经退行性疾病。CLN 7/MFSD 8基因编码溶酶体膜糖蛋白，但受CLN 7功能丧失影响的生化过程尚未探索，因此阻碍了潜在治疗的开发。在这里，我们发现，在CLN 7疾病的Cln 7小鼠模型中，自噬的失败导致结构和生物能量受损的神经元线粒体的积累。体内遗传学方法揭示了Cln 7 β ex 2神经元中线粒体活性氧（mROS）的升高，其介导糖酵解酶PFKFB 3活化并促成CLN 7发病机制。从机制上讲，mROS维持导致PFKFB 3蛋白稳定的信号级联反应，而PFKFB 3在健康神经元中通常不稳定。在体内Cln 7 pneumex 2小鼠脑和CLN 7患者来源的细胞中施用高选择性PFKFB 3抑制剂AZ 67纠正了关键疾病标志。因此，神经元中糖酵解酶PFKFB 3的异常上调可能有助于CLN 7发病机制，靶向PFKFB 3可以减轻这种和其他溶酶体贮积病。CLN 7神经元蜡样质脂褐质沉积症是一种遗传性溶酶体贮积病，通常在儿童期发作神经退行性症状。在这里，作者报告说，在CLN 7疾病的小鼠模型中，神经元活性氧和糖酵解酶PFKFB 3的活性增加，而PFKFB 3抑制改善了病理学特征。
CLN7 neuronal ceroid lipofuscinosis is an inherited lysosomal storage neurodegenerative disease highly prevalent in children. CLN7/MFSD8 gene encodes a lysosomal membrane glycoprotein, but the biochemical processes affected by CLN7-loss of function are unexplored thus preventing development of potential treatments. Here, we found, in the Cln7∆ex2 mouse model of CLN7 disease, that failure in autophagy causes accumulation of structurally and bioenergetically impaired neuronal mitochondria. In vivo genetic approach reveals elevated mitochondrial reactive oxygen species (mROS) in Cln7∆ex2 neurons that mediates glycolytic enzyme PFKFB3 activation and contributes to CLN7 pathogenesis. Mechanistically, mROS sustains a signaling cascade leading to protein stabilization of PFKFB3, normally unstable in healthy neurons. Administration of the highly selective PFKFB3 inhibitor AZ67 in Cln7∆ex2 mouse brain in vivo and in CLN7 patients-derived cells rectifies key disease hallmarks. Thus, aberrant upregulation of the glycolytic enzyme PFKFB3 in neurons may contribute to CLN7 pathogenesis and targeting PFKFB3 could alleviate this and other lysosomal storage diseases. CLN7 neuronal ceroid lipofuscinosis is an inherited lysosomal storage disease typically with childhood onset of neurodegenerative symptoms. Here the authors report that in a mouse model of CLN7 disease neuronal reactive oxygen species and the activity of glycolytic enzyme PFKFB3 are increased, while PFKFB3 inhibition ameliorates hallmarks of pathology.
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影响因子：
3.5
作者：
Brandenstein, Laura;Schweizer, Michaela;Storch, Stephan
通讯作者：
Storch, Stephan
影响因子：
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作者：
Herrero-Mendez, Angel;Almeida, Angeles;Bolanos, Juan P.
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作者：
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通讯作者：
Santorelli, Filippo M.
影响因子：
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作者：
LARRABEE, MG
通讯作者：
LARRABEE, MG