{Reference Type}: Journal Article
{Title}: Defective autophagy and increased apoptosis contribute toward the pathogenesis of FKRP-associated muscular dystrophies.
{Author}: Ortiz-Cordero C;Bincoletto C;Dhoke NR;Selvaraj S;Magli A;Zhou H;Kim DH;Bang AG;Perlingeiro RCR;
{Journal}: Stem Cell Reports
{Volume}: 16
{Issue}: 11
{Year}: 11 2021 9
{Factor}: 7.294
{DOI}: 10.1016/j.stemcr.2021.09.009
{Abstract}: Fukutin-related protein (FKRP) is a glycosyltransferase involved in glycosylation of alpha-dystroglycan (α-DG). Mutations in FKRP are associated with muscular dystrophies (MD) ranging from limb-girdle LGMDR9 to Walker-Warburg Syndrome (WWS), a severe type of congenital MD. Although hypoglycosylation of α-DG is the main hallmark of this group of diseases, a full understanding of the underlying pathophysiology is still missing. Here, we investigated molecular mechanisms impaired by FKRP mutations in pluripotent stem (PS) cell-derived myotubes. FKRP-deficient myotubes show transcriptome alterations in genes involved in extracellular matrix receptor interactions, calcium signaling, PI3K-Akt pathway, and lysosomal function. Accordingly, using a panel of patient-specific LGMDR9 and WWS induced PS cell-derived myotubes, we found a significant reduction in the autophagy-lysosome pathway for both disease phenotypes. In addition, we show that WWS myotubes display decreased ERK1/2 activity and increased apoptosis, which were restored in gene edited myotubes. Our results suggest the autophagy-lysosome pathway and apoptosis may contribute to the FKRP-associated MD pathogenesis.