Pompe disease, also known as glycogen storage disease type II, is caused by the lack or deficiency of a single enzyme, lysosomal acid alpha-glucosidase, leading to severe cardiac and skeletal muscle myopathy due to progressive accumulation of glycogen. The discovery that acid alpha-glucosidase resides in the lysosome gave rise to the concept of lysosomal storage diseases, and Pompe disease became the first among many monogenic diseases caused by loss of lysosomal enzyme activities. The only disease-specific treatment available for Pompe disease patients is enzyme replacement therapy (ERT) which aims to halt the natural course of the illness. Both the success and limitations of ERT provided novel insights in the pathophysiology of the disease and motivated the scientific community to develop the next generation of therapies that have already progressed to the clinic.
Pompe disease, a deficiency of glycogen-degrading lysosomal acid alpha-glucosidase (GAA), is a disabling multisystemic illness that invariably affects skeletal muscle in all patients. The patients still carry a heavy burden of the disease, despite the currently available enzyme replacement therapy. We have previously shown that progressive entrapment of glycogen in the lysosome in muscle sets in motion a whole series of “extra-lysosomal” events including defective autophagy and disruption of a variety of signaling pathways. Here, we report that metabolic abnormalities and energy deficit also contribute to the complexity of the pathogenic cascade. A decrease in the metabolites of the glycolytic pathway and a shift to lipids as the energy source are observed in the diseased muscle. We now demonstrate in a pre-clinical study that a recently developed replacement enzyme (recombinant human GAA; AT-GAA; Amicus Therapeutics) with much improved lysosome-targeting properties reversed or significantly improved all aspects of the disease pathogenesis, an outcome not observed with the current standard of care. The therapy was initiated in GAA-deficient mice with fully developed muscle pathology but without obvious clinical symptoms; this point deserves consideration.
Graphical AbstractMiT/TFE transcription factors are master regulators of cellular adaptation to a wide variety of stressful conditions. They control the expression of a plethora of genes involved in response to nutrient deprivation, oxidative and ER stress, and DNA and mitochondrial damage. MiT/TFE proteins play a critical role in organelle biogenesis, control of energy homeostasis, adaptation to pathogen infection, control of growth and development, aging, and death. MiT/TFE proteins are also modulators of critical signaling pathways that regulate cell proliferation, cellular fate commitment, and tumorigenesis. Many of these functions are evolutionary conserved from lower metazoans to mammals indicating that the adaptation to challenging conditions occurred early during evolution.
Polymorphisms in TLR4 gene were significantly associated with inflammatory bowel disease in North Indian population and they contribute in modulating transcription of inflammatory cytokines during UC leading to aberrant immune response.
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