Congenital muscular dystrophy with laminin α2 chain-deficiency Initiation of disease and development of treatment

Congenital muscle dystrophy type 1A (MDC1A) is a muscle disease caused by mutations in the LAMA2 gene, encoding the basement membrane protein laminin α2 chain. MDC1A patients exhibit neonatal onset of muscle weakness, progressive muscle wasting and hypotonia, joint contractures that mostly affect elbows, hips, knees and ankles along with scoliosis and delayed motor milestones. Currently, there is no cure for MDC1A and respiratory failure is the main cause of death. Patients with complete laminin α2 chain-deficiency have an early onset and also a more severe muscle phenotype whereas patients with partial loss usually have a milder disease course. The same genotype-phenotype correlations can be seen in the mouse models of MDC1A. The dy3K/dy3K knock-out model exhibits a much more severe phenotype than the dy2J/dy2J mouse model, which expresses a truncated laminin α2 chain. However, we have not before this thesis known how early the pathogenesis in the skeletal muscle starts. Here, we demonstrated that changes in skeletal muscle start with apoptosis already at day one after birth and inflammation at day four in dy3K/dy3K mice. Previously, it was demonstrated that the ubiquitin-proteasome system is upregulated in the dy3K/dy3K mouse muscle. Moreover, by inhibiting the proteasome by using a lab-bench drug, dy3K/dy3K mice exhibited reduced muscular dystrophy. This led us to testing an approved FDA drug, bortezomib, which also inhibits the proteasome. By using bortezomib we could partially ameliorate the disease in the dy3K/dy3K mice with an increased lifespan and improved muscle function. However, this could not be recapitulated in the dy2J/dy2J mice. Furthermore, in this thesis we also showed that another pathway for cellular degradation, the autophagy-lysosome pathway, is upregulated in the dy3K/dy3K mouse muscle. By inhibiting the autophagy pathway, dy3K/dy3K mice exhibited improved muscle morphology and increased lifespan. In summary, I have shown that there is enhanced proteasome and autophagy activity in MDC1A muscle and that proteasome and autophagy inhibitors, respectively, can be used to reduce disease in mice. I hope that our studies can form the basis for the development of clinically relevant autophagy inhibitors. It may also be worth testing bortezomib as a possible supportive therapy for MDC1A. Furthermore, our data suggest that treatment should be initiated as early as possible given that we detected disease changes already one to four days after birth in mice.