Center for Genomic Medicine and Department of Neurology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, MA, 02114, United States.
Georgia W. Woodruff School of Mechanical Engineering, Wallace H. Coulter Department of Biomedical Engineering, and Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, 30332, United States.
Neurosci Lett. 2021 Jun 11;755:135944. doi: 10.1016/j.neulet.2021.135944. Epub 2021 May 11.
Mucolipidosis IV (MLIV) is an autosomal-recessive disease caused by loss-of-function mutations in the MCOLN1 gene encoding the non-selective cationic lysosomal channel transient receptor potential mucolipin-1 (TRPML1). Patients with MLIV suffer from severe motor and cognitive deficits that manifest in early infancy and progressive loss of vision leading to blindness in the second decade of life. There are no therapies available for MLIV and the unmet medical need is extremely high. Here we review the spectrum of clinical presentations and the latest research in the MLIV pre-clinical model, with the aim of highlighting the progress in understanding the pathophysiology of the disease. These highlights include elucidation of the neurodevelopmental versus neurodegenerative features over the course of disease, hypomyelination as one of the major brain pathological disease hallmarks, and dysregulation of cytokines, with emerging evidence of IFN-gamma pathway upregulation in response to TRPML1 loss and pro-inflammatory activation of astrocytes and microglia. These scientific advances in the MLIV field provide a basis for future translational research, including biomarker and therapy development, that are desperately needed for this patient population.
黏脂贮积症 IV 型（MLIV）是一种常染色体隐性遗传病，由编码非选择性阳离子溶酶体通道瞬时受体电位黏脂素-1（TRPML1）的 MCOLN1 基因突变引起。MLIV 患者存在严重的运动和认知障碍，这些症状在婴儿早期就会显现，并逐渐出现视力丧失，导致患者在 20 岁左右失明。目前尚无 MLIV 的治疗方法，医疗需求尚未得到满足。本文回顾了 MLIV 的临床表现谱和临床前模型的最新研究，旨在强调对疾病病理生理学的认识进展。这些亮点包括阐明疾病过程中的神经发育与神经退行性特征、少突胶质细胞髓鞘形成缺陷作为主要的脑病理疾病特征之一，以及细胞因子失调，有证据表明 TRPML1 缺失后 IFN-γ 通路上调，星形胶质细胞和小胶质细胞呈炎症激活状态。MLIV 领域的这些科学进展为未来的转化研究提供了基础，包括生物标志物和治疗方法的开发，这对该患者群体是迫切需要的。
