Tobin Brendan R, Misko Albert, Miller-Browne Victoria, Sangster Madison, Grishchuk Yulia, Wood Levi B
School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, 315 Ferst Dr., Atlanta, GA 30332, USA.
Center for Genomic Medicine and Department of Neurology, Massachusetts General Hospital Research Institute, Harvard Medical School, 185 Cambridge St., Boston, MA 02114, USA.
Mol Ther Methods Clin Dev. 2025 Apr 24;33(2):101479. doi: 10.1016/j.omtm.2025.101479. eCollection 2025 Jun 12.
Mucolipidosis IV (MLIV) is an autosomal-recessive pediatric disease that leads to motor and cognitive deficits and loss of vision. It is caused by loss of function of the lysosomal channel transient receptor potential mucolipin-1, TRPML1, and is associated with an early brain phenotype consisting of glial reactivity, hypomyelination, and lysosomal abnormalities. Although the field is approaching the first translationally relevant therapy, we currently lack a molecular signature of disease that can be used to detect therapeutic efficacy. Here, we analyzed 7,322 proteins in the plasma proteome from 17 MLIV patients and 37 controls and compared protein profiles with clinical measures of disease severity (motor function, muscle tone, and age). We found a decrease in neuronal proteins and an increase in muscle proteins in MLIV, consistent with neuronal dysfunction and muscle pathology observed in patients. Reduced synaptic proteins (e.g., GABARAP) best correlated with disease severity. Comparing the MLIV plasma proteome to the brain proteome from the MLIV mouse model identified shared alterations in 45 proteins, including upregulated proteins related to lysosomal function (e.g., ACTN2, GLB1) and downregulated proteins related to myelination (e.g., TPPP3, CNTN2). These data indicate that peripheral blood plasma protein signatures mirror changes found in the MLIV brain.
黏脂贮积症IV型（MLIV）是一种常染色体隐性儿科疾病，会导致运动和认知缺陷以及视力丧失。它是由溶酶体通道瞬时受体电位黏脂蛋白-1（TRPML1）功能丧失引起的，与一种早期脑表型有关，该表型包括神经胶质反应性、髓鞘形成不足和溶酶体异常。尽管该领域正在接近首个具有转化相关性的疗法，但我们目前缺乏可用于检测治疗效果的疾病分子特征。在此，我们分析了17名MLIV患者和37名对照者血浆蛋白质组中的7322种蛋白质，并将蛋白质谱与疾病严重程度的临床指标（运动功能、肌张力和年龄）进行了比较。我们发现MLIV患者中神经元蛋白减少，肌肉蛋白增加，这与患者中观察到的神经元功能障碍和肌肉病变一致。突触蛋白（如GABARAP）减少与疾病严重程度的相关性最强。将MLIV血浆蛋白质组与MLIV小鼠模型的脑蛋白质组进行比较，发现45种蛋白质存在共同变化，包括与溶酶体功能相关的上调蛋白（如ACTN2、GLB1）和与髓鞘形成相关的下调蛋白（如TPPP3、CNTN2）。这些数据表明外周血血浆蛋白特征反映了MLIV脑中发现的变化。
