Ⅳ型粘脂症(MLIV)是一种表现为进行性智力障碍的溶酶体贮积病,运动障碍,过早死亡。目前没有治愈或矫正治疗。该疾病是由编码粘糖素-1的基因突变引起的,粘糖素-1是一种瞬时受体电位通道,被认为在溶酶体钙的排出中起关键作用。粘蛋白-1的缺失和随后的缺陷导致大量的细胞畸变,包括神经鞘糖脂(GSL)在神经元和其他细胞类型中的积累,小胶质细胞增生和,正如这里报道的,小脑浦肯野细胞丢失。一些研究表明,N-丁基脱氧野蓟霉素(NB-DNJ,也称为Miglustat),葡萄糖神经酰胺合酶(GCS)的抑制剂,成功地延迟了运动障碍的发作,提高寿命,并挽救一些小脑异常(例如,Purkinje细胞死亡)在另一种称为Niemann-PickC型(NPC)的溶酶体疾病中看到。鉴于MLIV和NPC在病理学上的相似性,我们检查了miglustat是否能有效改善MLIV患者的疾病进展.使用完整的mucolipin-1敲除小鼠(Mcoln1-/-),我们发现早期Miglustat治疗可延迟运动缺陷的发生和进展,延迟小脑浦肯野细胞的丢失,并减少MLIV疾病的小脑小胶质细胞增生特征。定量质谱分析提供了有关鼠MLIV脑组织GSL谱的新数据,并表明miglustat部分恢复了富含白质的脂质的野生型谱。总的来说,我们的发现表明,在MLIV小鼠模型中,早期的miglustat治疗延迟了临床相关病理的进展,因此支持考虑将米格卢司他作为人类MLIV疾病的治疗剂。
Mucolipidosis type IV (MLIV) is a lysosomal storage disease exhibiting progressive intellectual disability, motor impairment, and premature death. There is currently no cure or corrective treatment. The disease results from mutations in the gene encoding mucolipin-1, a transient receptor potential channel believed to play a key role in lysosomal calcium egress. Loss of mucolipin-1 and subsequent defects lead to a host of cellular aberrations, including accumulation of glycosphingolipids (GSLs) in neurons and other cell types, microgliosis and, as reported here, cerebellar Purkinje cell loss. Several studies have demonstrated that N-butyldeoxynojirimycin (NB-DNJ, also known as miglustat), an inhibitor of the enzyme glucosylceramide synthase (GCS), successfully delays the onset of motor deficits, improves longevity, and rescues some of the cerebellar abnormalities (e.g., Purkinje cell death) seen in another lysosomal disease known as Niemann-Pick type C (NPC). Given the similarities in pathology between MLIV and NPC, we examined whether miglustat would be efficacious in ameliorating disease progression in MLIV. Using a full mucolipin-1 knockout mouse (Mcoln1-/-), we found that early miglustat treatment delays the onset and progression of motor deficits, delays cerebellar Purkinje cell loss, and reduces cerebellar microgliosis characteristic of MLIV disease. Quantitative mass spectrometry analyses provided new data on the GSL profiles of murine MLIV brain tissue and showed that miglustat partially restored the wild type profile of white matter enriched lipids. Collectively, our findings indicate that early miglustat treatment delays the progression of clinically relevant pathology in an MLIV mouse model, and therefore supports consideration of miglustat as a therapeutic agent for MLIV disease in humans.