Enhanced lysosome biogenesis ameliorates neurodegenerative diseases

Abstract

Autolysosomes are formed by the fusion of autophagosomes and lysosomes, they maintain the cellular homeostasis as the scavengers to digest the cytosolic cargos, including lipids, proteins, glycogen, and even damaged organelles. Autophagosomes are double-membrane structure organelles. They generate from membrane nucleation, then expand and bend into a spherical shape by taking up other organelles’ membranes, such as plasma membrane, mitochondria, and endoplasmic reticulum. In this process, biological macromolecules and damaged organelles are sequestered into the autophagosomes. Lysosomes are single-membrane and acidified organelles. The mature lysosomes have the acidic lumen (pH 4.5-5.0) to provide a microenvironment for lysosomal hydrolase activity. To achieve the ultimate stage of cargo degradation, the lysosomes fuse the outer membrane of autophagosomes to form autolysosomes, and then disintegrated the inner membrane of autophagosomes and cargos. Autolysosomal dysfunctions lead to significantly declined degradation efficiency and result in the accumulation of macromolecules or damaged organelles, which subsequently cause metabolism dysregulation and aggravate the pathogenesis of human diseases.