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Lysosome damage and autophagy during neurodegenerative conditions
Published on February 27, 2020 21 min
Other Talks in the Series: Autophagy and Lysosomal Storage Diseases
Autophagy dysfunction in lysosomal storage disorders
- Dr. Carmine Settembre
- TIGEM (Telethon Institute of Genetics and Medicine), Italy
My name is Patricia Boya. I work at CIB-CSIC in Madrid, Spain. The title of my talk is "Lysosomal Damage and Autophagy During Neurodegenerative Conditions".
So this is the outline of today's talk. First, I will be introducing lysosomes and give the definition and functions. Then I will go to talk about lysosomes and cell death, and how lysosomal membrane permeabilization induces cell death. Methods to assess lysosomal membrane permeabilization. Inhibitors of lysosomal cell death. Then we'll give some examples of physiological examples of lysosomal cell death. Then I will talk about lysosomal cell death during neurodegeneration, and then give you a specific example of work done in our lab regarding lysosomes and cell death during retinal degeneration. I will finish my talk talking about neuroprotective strategies for lysosomal cell death.
This image displays the cells lysosomes labeled in red after staining with the dye Acridine orange. Lysosomes are membrane-bound organelles that are found in our cells. They have an acidic pH that is maintained by the vacuolar ATPase. Lysosomes are filled of acidic hydrolases such as proteases, lipases, and DNAases that are in charge of the control digestion of macromolecules.
Depending on how the material to be degraded reaches the lysosomes, we can distinguish between heterophagy, when it is extracellular material, and autophagy, when the material to be degraded comes from the inside of the cell. Heterophagy delivers the lysosome material for degradation, such as bacteria and apoptotic cells. Autophagy is classified into several forms. Macroautophagy, which is characterized by the formation of an intermediate organelle, the autophagosome, which enwraps cytoplasmic component including entire organelles. Then the good material is then degraded upon fusion of the autophagosome with a lysosome. In chaperone-mediated autophagy, proteins bearing the KFERQ motif are specifically delivered to the lysosome via interaction with the chaperone proteins, such as Hsp70. This molecule in turn interacts with LAMP-2A, a receptor found on the lysosomal membrane, and triggers the unfolding and translocation of the protein inside the lysosomal lumen. Finally, microautophagy involves the direct transportation into the lysosome of molecules selected for degradation.