The autophagy-lysosomal pathway General concepts and clinical implications

Neurons, like other eukaryotic cells, utilize 2 major pathways for turning over dysfunctional proteins or organelles. One of them is the ubiquitin-proteasome system, which degrades short-lived proteins in the cytoplasm and nucleus and involves the covalent binding of ubiquitin molecules to the targeted protein, followed by its degradation by the proteasome. The second is the autophagy-lysosome pathway, which digests long-lived proteins, protein aggregates, stress RNA granules, and abnormal cytoplasmic organelles, including mitochondria. Autophagy (derived from the Greek words for self and eating) includes 3 major types: microautophagy, chaperone-mediated autophagy (CMA), and macroautophagy; all these pathways eventually lead to cargo degradation by the lysosome. Autophagy is a highly regulated process that involves sequential activation of protein complexes encoded by autophagic genes (ATG). Macroautophagy, the best-characterized form of autophagy, involves the formation of a particular organelle called autophagosome. There are 2 main types of macroautophagy. Basal macroautophagy is a quality control mechanism that prevents metabolic and oxidative stress by degrading aggregated or aggregate-prone proteins or damaged organelles, such as mitochondria. Starvation-induced autophagy occurs in response to nutrient deprivation and recycles macromolecules to provide substrates for energy metabolism. The mammalian (mechanistic) target of rapamycin complex 1 (mTORC1) constitutively inhibits starvation-induced and to a lesser extent basal autophagy. There is interaction between the ubiquitin and the autophagy systems, as ubiquitination serves as a signal for cargo-selective autophagy. There is also crosstalk between autophagy and apoptosis; in most cases, autophagy precedes and increases threshold for apoptosis in response to cellular stress. The fusion of the autophagosome with the lysosome is a critical final step of autophagy. Impairment of the autophagy-lysosomal system leads to accumulation of abnormal protein aggregates and dysfunctional mitochondria promoting oxidative stress and apoptosis. These are shared mechanisms of cell death in neurodegenerative disorders and lysosomal storage diseases. There are recent comprehensive reviews on these subjects  and only salient concepts are emphasized here.

Neurology 2015