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Review
.2020 Mar 2;12(3):a033993.
doi: 10.1101/cshperspect.a033993.

The Autophagy Lysosomal Pathway and Neurodegeneration

Affiliations
Review

The Autophagy Lysosomal Pathway and Neurodegeneration

Steven Finkbeiner. Cold Spring Harb Perspect Biol..

Abstract

The autophagy lysosomal pathway (ALP) is a major mechanism for degrading intracellular macromolecules. The catabolic products can then be used by the cell for energy or as building blocks to make other macromolecules. Since its discovery, a variety of cellular pathways have emerged that target components with varying specificity for lysosomal degradation. Under some circumstances, lysosomes may release their contents into the extracellular space where they may serve signaling or pathogenic functions. The ALP is active in healthy cells, and the level of activity can be regulated by nutrient-sensing and metabolic signaling pathways. The ALP is the primary pathway by which lipids and damaged organelles are degraded and may be the only pathway capable of degrading aggregated proteins. As such, there has been intense interest in understanding the role of the ALP in the accumulation of aggregated misfolded proteins characteristic of many of the major adult-onset neurodegenerative diseases. This review focuses on recent advances in our understanding of the ALP and its potential relationship to the pathogenesis and treatment of neurodegenerative diseases.

Copyright © 2020 Cold Spring Harbor Laboratory Press; all rights reserved.

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Figures

Figure 1.
Figure 1.
The autophagy lysosomal pathway. The lysosome is the hub of a network of pathways that feed cargo into its lumen for degradation. These include pathways depicted here to deliver intracellular cargo such as macroautophagy, chaperone-mediated autophagy and microautophagy, as well as others that deliver extracellular cargo to the lysosome including endocytosis and micropinocytosis (see text for details). Cargo delivered to the lysosome can undergo degradation into molecular building blocks that can return to the cytoplasm to be catabolized further to supply cellular energy needs or to be reused in the synthesis of new macromolecules. Contents of lysosomes can also be extruded extracellularly by a Ca2+-dependent exocytic process. LAMP2A, Lysosome-associated membrane glycoprotein 2; HSC70, heat shock cognate 71.
Figure 2.
Figure 2.
Genetic links between autophagy and neurodegenerative disease. Mutations in many genes that encode proteins that play a role in the autophagy lysosomal pathway (ALP) lead to neurodegenerative disease syndromes in humans, indicating that impairment of the ALP can be sufficient to produce neurodegenerative disease. Some examples are shown in this figure. AD, Alzheimer's disease; ALS/FTD, amyotrophic lateral sclerosis/frontotemporal dementia; BPAN, β-propeller protein-associated neurodegeneration; CMT2, Charcot-Marie-Tooth disease 2; HD, Huntington's disease; HSP, hereditary spastic paraplegia; PD, Parkinson's disease.
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