Trehalose reduces retinal degeneration, neuroinflammation and storage burden caused by a lysosomal hydrolase deficiency.
Trehalose reduces retinal degeneration, neuroinflammation and storage burden caused by a lysosomal hydrolase deficiency.
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DOI：
10.1080/15548627.2018.1474313
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发表时间：
2018
期刊：
影响因子：
13.3
通讯作者：
Sardiello M
中科院分区：
文献类型：
--
作者：
Lotfi P;Tse DY;Di Ronza A;Seymour ML;Martano G;Cooper JD;Pereira FA;Passafaro M;Wu SM;Sardiello M
未降解分子物质的积累导致许多溶酶体贮积症（LSD）中的进行性神经变性，这些溶酶体贮积症是由溶酶体水解酶的功能缺陷引起的。为了确定通过小分子疗法诱导大自噬/自噬是否对由于酶缺乏引起的神经病性LSD有效，我们用自噬诱导化合物海藻糖治疗粘多糖沉积症IIIB（MPS IIIB）的小鼠模型，所述粘多糖沉积症IIIB是由酶NAGLU（α-N-乙酰葡糖胺糖苷酶[Sanfilippo病IIIB]）缺乏引起的储存障碍。经过治疗的naglu-/ -小鼠寿命更长，表现出更少的多动症和焦虑，保留了它们的视力（和视网膜光感受器），并表现出大脑和视网膜炎症减少。经处理的小鼠还显示神经元和神经胶质细胞中自噬空泡的清除得到改善，伴随着控制溶酶体生物发生和自噬通量的TFEB转录网络的激活。因此，小分子诱导的自噬增强可以改善与溶酶体酶缺乏相关的神经症状，并可以为神经性LSD提供可行的治疗方法。缩略语：方差分析：方差分析; Atg 7：自噬相关7例; AV：自噬泡; CD68：cd 68抗原; ERG：视网膜电图; ERT：酶替代疗法;- 你是谁？甘油醛-3-磷酸脱氢酶; GFAP：胶质细胞酸性蛋白; GNAT 2：鸟嘌呤核苷酸结合蛋白，α转导2; HSCT：造血干细胞移植; INL：内核层; LC 3：微管相关蛋白1轻链3 α; MPS：粘多糖; NAGLU：α-N-乙酰氨基葡萄糖苷酶（Sanfilippo病IIIB）; ONL：外核层; PBS：磷酸盐缓冲盐水; PRKCA/PKCα：蛋白激酶C，α; S1 BF：体感皮层; SQSTM 1：隔离体1; TEM：透射电子显微镜; TFEB：转录因子EB; VMP/VPL：丘脑腹后核
The accumulation of undegraded molecular material leads to progressive neurodegeneration in a number of lysosomal storage disorders (LSDs) that are caused by functional deficiencies of lysosomal hydrolases. To determine whether inducing macroautophagy/autophagy via small-molecule therapy would be effective for neuropathic LSDs due to enzyme deficiency, we treated a mouse model of mucopolysaccharidosis IIIB (MPS IIIB), a storage disorder caused by deficiency of the enzyme NAGLU (alpha-N-acetylglucosaminidase [Sanfilippo disease IIIB]), with the autophagy-inducing compound trehalose. Treated naglu–/ – mice lived longer, displayed less hyperactivity and anxiety, retained their vision (and retinal photoreceptors), and showed reduced inflammation in the brain and retina. Treated mice also showed improved clearance of autophagic vacuoles in neuronal and glial cells, accompanied by activation of the TFEB transcriptional network that controls lysosomal biogenesis and autophagic flux. Therefore, small-molecule-induced autophagy enhancement can improve the neurological symptoms associated with a lysosomal enzyme deficiency and could provide a viable therapeutic approach to neuropathic LSDs. Abbreviations: ANOVA: analysis of variance; Atg7: autophagy related 7; AV: autophagic vacuoles; CD68: cd68 antigen; ERG: electroretinogram; ERT: enzyme replacement therapy; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFAP: glial fibrillary acidic protein; GNAT2: guanine nucleotide binding protein, alpha transducing 2; HSCT: hematopoietic stem cell transplantation; INL: inner nuclear layer; LC3: microtubule-associated protein 1 light chain 3 alpha; MPS: mucopolysaccharidoses; NAGLU: alpha-N-acetylglucosaminidase (Sanfilippo disease IIIB); ONL: outer nuclear layer; PBS: phosphate-buffered saline; PRKCA/PKCα: protein kinase C, alpha; S1BF: somatosensory cortex; SQSTM1: sequestosome 1; TEM: transmission electron microscopy; TFEB: transcription factor EB; VMP/VPL: ventral posterior nuclei of the thalamus
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DOI：
10.1016/j.bbrc.2008.06.094
发表时间：
2008-09-12
影响因子：
3.1
作者：
Beranger, Florence;Crozet, Carole;Lehmann, Sylvain
通讯作者：
Lehmann, Sylvain
DOI：
10.1073/pnas.1416660111
发表时间：
2014-10-14
影响因子：
11.1
作者：
Kan, Shih-hsin;Aoyagi-Scharber, Mika;Neufeld, Elizabeth F.
通讯作者：
Neufeld, Elizabeth F.
影响因子：
3.7
作者：
Fernandez-Estevez MA;Casarejos MJ;López Sendon J;Garcia Caldentey J;Ruiz C;Gomez A;Perucho J;de Yebenes JG;Mena MA
通讯作者：
Mena MA
影响因子：
5.3
作者：
Cearley, Cassia N.;Wolfe, John H.
通讯作者：
Wolfe, John H.
DOI：
10.1073/pnas.1305623110
发表时间：
2013-05-07
影响因子：
11.1
作者：
Decressac, Mickael;Mattsson, Bengt;Bjorklund, Anders
通讯作者：
Bjorklund, Anders