Lysosomes and the pathogenesis of merosin-deficient congenital muscular dystrophy

Congenital muscular dystrophy type 1A (MDC1A), the most common congenital muscular dystrophy in Western countries, is caused by recessive mutations in LAMA2, the gene encoding laminin alpha 2. Currently, no cure or disease modifying therapy has been successfully developed for MDC1A. Examination of patient muscle biopsies revealed altered distribution of lysosomes. We hypothesized that this redistribution was a novel and potentially druggable aspect of disease pathogenesis. We explored this hypothesis using candyfloss (caf), a zebrafish model of MDC1A. We found that lysosome distribution in caf zebrafish was also abnormal. This altered localization was significantly associated with fiber detachment and could be prevented by blocking myofiber detachment. Overexpression of transcription factor EB, a transcription factor that promotes lysosomal biogenesis, led to increased lysosome content and decreased fiber detachment. We conclude that genetic manipulation of the lysosomal compartment is able to alter the caf zebrafish disease process, suggesting that lysosome function may be a target for disease modification.

Automated summary

Congenital muscular dystrophy type 1A (MDC1A) is a common genetic disorder caused by mutations in the LAMA2 gene. In this study, researchers used a zebrafish model to investigate the role of lysosome distribution in MDC1A. They found that abnormal lysosome distribution was associated with fiber detachment and could be improved by overexpression of a transcription factor called transcription factor EB. This suggests that targeting lysosome function may be a potential therapeutic strategy for treating MDC1A.