Impaired myelination and reduced brain ferric iron in the mouse model of mucolipidosis IV.
Impaired myelination and reduced brain ferric iron in the mouse model of mucolipidosis IV.
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DOI：
10.1242/dmm.021154
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发表时间：
2015-12
影响因子：
4.3
通讯作者：
Slaugenhaupt SA
中科院分区：
文献类型：
--
作者：
Grishchuk Y;Peña KA;Coblentz J;King VE;Humphrey DM;Wang SL;Kiselyov KI;Slaugenhaupt SA
IV型粘脂沉积症（MLIV）是一种由MCOLN 1基因突变引起的溶酶体贮积病，MCOLN 1基因编码溶酶体瞬时受体电位离子通道粘脂蛋白-1（TRPML 1）。MLIV导致运动和认知发育受损、视力进行性丧失和胃无氯血症。TRPML 1缺失如何导致严重的精神发育迟滞目前尚不清楚，MLIV也没有治疗方法。白色物质异常和胼胝体发育不良是MLIV脑病理学的主要标志。在这里，我们报告说，小鼠中TRPML 1的缺失会导致成熟不足和少突胶质细胞的缺失，从而导致脑髓鞘形成的发育异常。在出生后第10天，Mcoln 1 −/−小鼠的髓鞘形成缺陷是明显的，这是小鼠大脑中出生后髓鞘形成的活跃阶段。Mcoln 1-/-小鼠出生后第10天成熟少突胶质细胞标记物的表达减少，并在整个疾病过程中保持较低水平。我们观察到Mcoln 1 −/−脑中的Perls染色减少，表明三价铁水平较低。未灌注脑中的总铁含量在Mcoln 1 −/−和野生型同窝小鼠之间没有显著差异，这表明观察到的少突胶质细胞成熟延迟或丢失可能是由铁处理受损引起的，而不是由整体缺铁引起的。总的来说，这些数据强调MLIV的发展而不是退行性疾病过程，并建议应该更加关注少突胶质细胞的成熟和存活，以更好地了解MLIV的发病机制和帮助治疗发展。总结：编码瞬时受体电位通道粘脂蛋白-1（TRPML 1）的MCOLN 1基因的功能缺失突变导致破坏性溶酶体贮积症，粘脂沉积症IV。在这里，我们报告说，TRPML 1在小鼠的损失会导致脑髓鞘形成的发育畸变。
Mucolipidosis type IV (MLIV) is a lysosomal storage disease caused by mutations in the MCOLN1 gene, which encodes the lysosomal transient receptor potential ion channel mucolipin-1 (TRPML1). MLIV causes impaired motor and cognitive development, progressive loss of vision and gastric achlorhydria. How loss of TRPML1 leads to severe psychomotor retardation is currently unknown, and there is no therapy for MLIV. White matter abnormalities and a hypoplastic corpus callosum are the major hallmarks of MLIV brain pathology. Here, we report that loss of TRPML1 in mice results in developmental aberrations of brain myelination as a result of deficient maturation and loss of oligodendrocytes. Defective myelination is evident in Mcoln1−/− mice at postnatal day 10, an active stage of postnatal myelination in the mouse brain. Expression of mature oligodendrocyte markers is reduced in Mcoln1−/− mice at postnatal day 10 and remains lower throughout the course of the disease. We observed reduced Perls' staining in Mcoln1−/− brain, indicating lower levels of ferric iron. Total iron content in unperfused brain is not significantly different between Mcoln1−/− and wild-type littermate mice, suggesting that the observed maturation delay or loss of oligodendrocytes might be caused by impaired iron handling, rather than by global iron deficiency. Overall, these data emphasize a developmental rather than a degenerative disease course in MLIV, and suggest that there should be a stronger focus on oligodendrocyte maturation and survival to better understand MLIV pathogenesis and aid treatment development. Summary: Loss-of-function mutations in the MCOLN1 gene encoding transient receptor potential channel mucolipin-1 (TRPML1) result in a devastating lysosomal storage disorder, mucolipidosis IV. Here, we report that loss of TRPML1 in mice causes developmental aberrations of brain myelination.