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

Sammanfattning: Congenital muscle dystrophy type 1A (MDC1A) is a muscle disease caused bymutations in the LAMA2 gene, encoding the basement membrane protein lamininα2 chain. MDC1A patients exhibit neonatal onset of muscle weakness, progressivemuscle 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 amore severe muscle phenotype whereas patients with partial loss usually have amilder disease course. The same genotype-phenotype correlations can be seen inthe mouse models of MDC1A. The dy3K/dy3K knock-out model exhibits a muchmore severe phenotype than the dy2J/dy2Jmouse model, which expresses atruncated laminin α2 chain. However, we have not before this thesis known howearly the pathogenesis in the skeletal muscle starts. Here, we demonstrated thatchanges in skeletal muscle start with apoptosis already at day one after birth andinflammation at day four in dy3K/dy3K mice.Previously, it was demonstrated that the ubiquitin-proteasome system isupregulated in the dy3K/dy3K mouse muscle. Moreover, by inhibiting theproteasome by using a lab-bench drug, dy3K/dy3Kmice exhibited reduced musculardystrophy. This led us to testing an approved FDA drug, bortezomib, which alsoinhibits the proteasome. By using bortezomib we could partially ameliorate thedisease in the dy3K/dy3Kmice with an increased lifespan and improved musclefunction. However, this could not be recapitulated in the dy2J/dy2J mice.Furthermore, in this thesis we also showed that another pathway for cellulardegradation, the autophagy-lysosome pathway, is upregulated in thedy3K/dy3Kmouse muscle. By inhibiting the autophagy pathway, dy3K/dy3K miceexhibited improved muscle morphology and increased lifespan. In summary, Ihave shown that there is enhanced proteasome and autophagy activity in MDC1Amuscle and that proteasome and autophagy inhibitors, respectively, can be used toreduce disease in mice. I hope that our studies can form the basis for thedevelopment of clinically relevant autophagy inhibitors. It may also be worthtesting bortezomib as a possible supportive therapy for MDC1A. Furthermore, ourdata suggest that treatment should be initiated as early as possible given that wedetected disease changes already one to four days after birth in mice.