Center for Genomic Medicine and Department of Neurology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA 02114, USA.
Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Dis Model Mech. 2020 Jul 30;13(7):dmm044230. doi: 10.1242/dmm.044230.
Mucolipidosis type IV (MLIV) is a lysosomal disease caused by mutations in the gene that encodes the endolysosomal transient receptor potential channel mucolipin-1, or TRPML1. MLIV results in developmental delay, motor and cognitive impairments, and vision loss. Brain abnormalities include thinning and malformation of the corpus callosum, white-matter abnormalities, accumulation of undegraded intracellular 'storage' material and cerebellar atrophy in older patients. Identification of the early events in the MLIV course is key to understanding the disease and deploying therapies. The mouse model reproduces all major aspects of the human disease. We have previously reported hypomyelination in the MLIV mouse brain. Here, we investigated the onset of hypomyelination and compared oligodendrocyte maturation between the cortex/forebrain and cerebellum. We found significant delays in expression of mature oligodendrocyte markers , and in the cortex, manifesting as early as 10 days after birth and persisting later in life. Such delays were less pronounced in the cerebellum. Despite our previous finding of diminished accumulation of the ferritin-bound iron in the brain, we report no significant changes in expression of the cytosolic iron reporters, suggesting that iron-handling deficits in MLIV occur in the lysosomes and do not involve broad iron deficiency. These data demonstrate very early deficits of oligodendrocyte maturation and critical regional differences in myelination between the forebrain and cerebellum in the mouse model of MLIV. Furthermore, they establish quantitative readouts of the MLIV impact on early brain development, useful to gauge efficacy in pre-clinical trials.
黏脂贮积症 IV 型（MLIV）是一种溶酶体疾病，由编码内溶酶体瞬时受体电位通道黏脂素-1（TRPML1）的基因突变引起。MLIV 导致发育迟缓、运动和认知障碍以及视力丧失。脑异常包括胼胝体变薄和畸形、白质异常、未降解的细胞内“储存”物质积累以及老年患者的小脑萎缩。识别 MLIV 病程中的早期事件是理解疾病和部署治疗方法的关键。小鼠模型再现了人类疾病的所有主要方面。我们之前报道过 MLIV 小鼠大脑中的少突胶质细胞发育不全。在这里，我们研究了少突胶质细胞发育不全的发病机制，并比较了大脑皮层/前脑和小脑之间的少突胶质细胞成熟情况。我们发现成熟少突胶质细胞标志物 和 在大脑皮层中的表达明显延迟，早在出生后 10 天就出现，并持续到生命后期。小脑中的这种延迟不太明显。尽管我们之前发现 MLIV 大脑中结合铁的铁蛋白积累减少，但我们报告称细胞溶质铁报告器的表达没有明显变化，这表明 MLIV 中的铁处理缺陷发生在溶酶体中，而不涉及广泛的铁缺乏。这些数据表明 MLIV 小鼠模型中前脑和小脑之间的少突胶质细胞成熟存在非常早期的缺陷和髓鞘形成的关键区域差异。此外，它们建立了 MLIV 对早期大脑发育影响的定量读数，有助于在临床前试验中评估疗效。
