Reinhard Judith R, Porrello Emanuela, Lin Shuo, Pelczar Pawel, Previtali Stefano C, Rüegg Markus A
Biozentrum, University of Basel, 4056 Basel, Switzerland.
Neuromuscular Repair Unit, InSpe and Division of Neuroscience, IRCCS Ospedale San Raffaele, 20132 Milano, Italy.
PNAS Nexus. 2023 Mar 15;2(4):pgad083. doi: 10.1093/pnasnexus/pgad083. eCollection 2023 Apr.
-related muscular dystrophy (LAMA2 MD or MDC1A) is a devastating congenital muscular dystrophy that is caused by mutations in the gene encoding laminin-α2, the long chain of several heterotrimeric laminins. Laminins are essential components of the extracellular matrix that interface with underlying cells. The pathology of LAMA2 MD patients is dominated by an early-onset, severe muscular dystrophy that ultimately leads to death by respiratory insufficiency. However, pathology in nonmuscle tissues has been described. Prior work in the / mouse model for LAMA2 MD has shown that two linker proteins, mini-agrin and αLNNd, when expressed in skeletal muscle fibers, greatly increase survival from a few months up to more than 2 years. However, the restoration of skeletal muscle function accentuates the pathology in nonmuscle tissue in / mice, first and foremost in the peripheral nerve resulting in paralysis of the hind limbs. We now show that the expression of the two linker proteins in all tissues ameliorates the muscular dystrophy and prevents the appearance of the hind limb paralysis. Importantly, the same ameliorating effect of the linker proteins was seen in / mice, which represent the most severe mouse model of LAMA2 MD. In summary, these data show that the two linker proteins can compensate the loss of laminin-α2 in muscle and peripheral nerve, which are the two organs most affected in LAMA2 MD. These results are of key importance for designing appropriate expression constructs for mini-agrin and αLNNd to develop a gene therapy for LAMA2 MD patients.
层粘连蛋白α2相关的肌营养不良症（LAMA2 MD或MDC1A）是一种严重的先天性肌营养不良症，由编码层粘连蛋白α2（几种异源三聚体层粘连蛋白的长链）的基因突变引起。层粘连蛋白是细胞外基质与下层细胞相互作用的重要组成部分。LAMA2 MD患者的病理特征主要是早发性、严重的肌营养不良症，最终导致呼吸功能不全死亡。然而，非肌肉组织中的病理情况已有描述。先前在LAMA2 MD的/小鼠模型中的研究表明，两种连接蛋白，小聚集蛋白和αLNNd，当在骨骼肌纤维中表达时，可将存活率从几个月大幅提高到两年多。然而，骨骼肌功能的恢复加剧了/小鼠非肌肉组织中的病理变化，首先是外周神经，导致后肢麻痹。我们现在表明，这两种连接蛋白在所有组织中的表达改善了肌营养不良症，并防止了后肢麻痹的出现。重要的是，在/小鼠中也观察到了连接蛋白的相同改善效果，/小鼠代表了LAMA2 MD最严重的小鼠模型。总之，这些数据表明，这两种连接蛋白可以补偿肌肉和外周神经中层粘连蛋白α2的缺失，这两个器官在LAMA2 MD中受影响最大。这些结果对于设计合适的小聚集蛋白和αLNNd表达构建体以开发针对LAMA2 MD患者的基因治疗至关重要。
