Clin Exp Allergy. and periventricular white matter abnormalities.[160, 161]extends mouse lifespan??Intramuscular AAV9-DES-corrects neuromuscular junction pathology. Open in a separate window Note that older citations are not included C rather the intent of this table to update the reader on recent publications. Lysosomes and autophagy in Pompe disease Lysosomes are defined as membrane-bound organelles with acidic interior made up of a collection of specific hydrolytic enzymes capable of breaking down a variety of macromolecules such as proteins, nucleic acids, lipids, and carbohydrates. A common hallmark of a large group of over 70 lysosomal JAK1-IN-7 storage diseases (LSDs) is the accumulation of undigested substrates within the lysosomal lumen, leading to lysosomal expansion . For years, progressive disruption of this basic degradative function of the lysosome was considered an adequate explanation of the pathogenesis of LSDs, including Pompe disease C the first recognized storage disorder linked to the lysosome . However, this long-held view of lysosomes as terminal degradation compartments is now a thing of the past. Instead, the lysosome is viewed as a sophisticated cellular center that controls a variety of cellular processes including cell growth, signaling, nutrient sensing, and autophagy [35, 36]. Macroautophagy (commonly referred to as autophagy) is usually a fundamental, evolutionarily ancient process that mediates JAK1-IN-7 the transfer of intracellular materials to lysosomes for degradation. The process involves the formation of double-membrane vesicles, called autophagosomes, that sequester the cargo destined for degradation [37C40]. Autophagosomes fuse with lysosomes where the engulfed portion of cytoplasm is usually broken down and the resulting building blocks (e.g., amino acids, glucose, nucleotides, fatty acids) are exported back into the cytosol and utilized for energy generation and in biosynthetic pathways . Initially, autophagy was described as a survival mechanism in response to cellular stressors, in particular amino acid starvation; induction of autophagy under nutrient-poor conditions allows the cell to derive new amino acids and energy from the random, nonselective (bulk) degradation of cellular components . This Oaz1 response to environmental signals is usually mediated by JAK1-IN-7 the concerted actions of the mammalian target of rapamycin complex 1 (mTORC1), the grasp nutrient sensor and growth regulator, and AMPCactivated protein kinase (AMPK), which is a key energy sensor. When nutrients are abundant, mTORC1 is usually recruited and activated at the lysosomal surface [43, 44]; once active, mTORC1 inhibits autophagy by phosphorylating autophagy-initiating kinase Ulk1. In contrast, when nutrients are insufficient, activated AMPK stimulates autophagy indirectly, by inhibiting mTORC1 (through phosphorylation of TSC2), and directly, by phosphorylating Ulk1 on distinct sites [45, 46]. Moreover, under nutritent-poor conditions, the inactive mTORC1 is usually detached from the lysosome and promotes autophagy by allowing translocation of transcription factors EB and E3 (TFEB and TFE3) to the nucleus where they activate genes involved in lysosomal and autophagosomal biogenesis [36, 47C50]. In addition to starvation-induced autophagy, autophagic machinery functions at low baseline levels to maintain cellular homeostasis by specifically recognizing and eliminating protein aggregates and damaged organelles [51, 52]. Based on the organelle destined for elimination, selective autophagy is called mitophagy (for mitochondria), lysophagy (for lysosomes), lipophagy (for lipid droplets), etc. Autophagic degradation of glycogen, a process termed glycophagy, was shown to have a critical importance in newborns [53C55]. Thus, the autophagy-lysosomal pathway plays a crucial role in the removal of JAK1-IN-7 worn-out organelles and toxic components as well as in cellular adaptation to various stresses and starvation. Dysfunctional autophagy has been associated with a range of pathologies including cancer, neurodegeneration, metabolic and JAK1-IN-7 cardiac diseases, and not surprisingly, LSDs including Pompe disease [56, 57]. The process is particularly important for the survival and stress adaptation of post-mitotic cells like neurons or muscle cells that are most affected in Pompe disease. Considering the evolving role of lysosomes, it is now amply clear that lysosomal dysfunction in the diseased muscle cells initiates a cascade of.