Unitat de Fisiologia, Departament de Ciències Fisiològiques, Genes Disease and Therapy Program IDIBELL-Institute of Neurosciences, Universitat de Barcelona, L'Hospitalet de Llobregat, 08907 Barcelona, Spain.
Unitat de Genètica, Departament de Ciències Fisiològiques, Genes Disease and Therapy Program IDIBELL-Institute of Neurosciences, Universitat de Barcelona, L'Hospitalet de Llobregat, 08907 Barcelona, Spain.
Int J Mol Sci. 2022 May 16;23(10):5528. doi: 10.3390/ijms23105528.
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare type of vacuolating leukodystrophy (white matter disorder), which is mainly caused by defects in MLC1 or glial cell adhesion molecule (GlialCAM) proteins. In addition, autoantibodies to GlialCAM are involved in the pathology of multiple sclerosis. and genes encode for membrane proteins of unknown function, which has been linked to the regulation of different ion channels and transporters, such as the chloride channel VRAC (volume regulated anion channel), ClC-2 (chloride channel 2), and connexin 43 or the Na/K-ATPase pump. However, the mechanisms by which MLC proteins regulate these ion channels and transporters, as well as the exact function of MLC proteins remain obscure. It has been suggested that MLC proteins might regulate signalling pathways, but the mechanisms involved are, at present, unknown. With the aim of answering these questions, we have recently described the brain GlialCAM interactome. Within the identified proteins, we could validate the interaction with several G protein-coupled receptors (GPCRs), including the orphan GPRC5B and the proposed prosaposin receptors GPR37L1 and GPR37. In this review, we summarize new aspects of the pathophysiology of MLC disease and key aspects of the interaction between GPR37 receptors and MLC proteins.
巨脑性脑白质营养不良伴皮质下囊肿（MLC）是一种罕见的空泡性脑白质营养不良（白质疾病），主要由 MLC1 或神经胶质细胞黏附分子（GlialCAM）蛋白缺陷引起。此外，针对 GlialCAM 的自身抗体参与了多发性硬化症的病理过程。和 基因编码具有未知功能的膜蛋白，这些蛋白与不同离子通道和转运体的调节有关，如氯离子通道 VRAC（体积调节阴离子通道）、ClC-2（氯离子通道 2）和连接蛋白 43 或 Na/K-ATP 酶泵。然而，MLC 蛋白调节这些离子通道和转运体的机制以及 MLC 蛋白的确切功能仍然不清楚。有人提出 MLC 蛋白可能调节信号通路，但目前尚不清楚涉及的机制。为了回答这些问题，我们最近描述了大脑 GlialCAM 相互作用组。在鉴定出的蛋白质中，我们可以验证与几种 G 蛋白偶联受体（GPCR）的相互作用，包括孤儿 GPRC5B 和拟定位蛋白受体 GPR37L1 和 GPR37。在这篇综述中，我们总结了 MLC 疾病病理生理学的新方面和 GPR37 受体与 MLC 蛋白相互作用的关键方面。
