Heparan Sulfate Structure Affects Autophagy, Lifespan, Responses to Oxidative Stress, and Cell Degeneration in Drosophila parkin Mutants
| Autor: | Claire Reynolds-Peterson, Jennifer Dobson, Claire Trasorras, Scott B. Selleck, Mei Jiang, Nicholas Schultheis, Jie Xu, Hidenao Toyoda, Akiko Kinoshita-Toyoda, Casey Cruse, Brandon Yonel, Na Zhao |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
autophagy
Ubiquitin-Protein Ligases Longevity Mitochondrion Biology QH426-470 Investigations Presenilin Parkin 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Mitophagy medicine Genetics heparan sulfate modified proteins presenilin Animals Drosophila Proteins parkin Compound Eye Arthropod Molecular Biology Genetics (clinical) 030304 developmental biology Heparan Sulfate Biosynthesis 0303 health sciences Muscles Neurodegeneration Autophagy Presenilins Brain Heparan sulfate medicine.disease Cell biology Oxidative Stress mitophagy Drosophila melanogaster chemistry Mutation Heparitin Sulfate 030217 neurology & neurosurgery |
| Zdroj: | G3: Genes|Genomes|Genetics G3: Genes, Genomes, Genetics, Vol 10, Iss 1, Pp 129-141 (2020) |
| ISSN: | 2160-1836 |
| Popis: | Autophagy is a catabolic process that provides cells with energy and molecular building blocks during nutritional stress. Autophagy also removes misfolded proteins and damaged organelles, a critical mechanism for cellular repair. Earlier work demonstrated that heparan sulfate proteoglycans, an abundant class of carbohydrate-modified proteins found on cell surfaces and in the extracellular matrix, suppress basal levels of autophagy in several cell types during development in Drosophila melanogaster. In studies reported here, we examined the capacity of heparan sulfate synthesis to influence events affected by autophagy, including lifespan, resistance to reactive oxygen species (ROS) stress, and accumulation of ubiquitin-modified proteins in the brain. Compromising heparan sulfate synthesis increased autophagy-dependent processes, evident by extended lifespan, increased resistance to ROS, and reduced accumulation of ubiquitin-modified proteins in the brains of ROS exposed adults. The capacity of altering heparan sulfate biosynthesis to protect cells from injury was also evaluated in two different models of neurodegeneration, overexpression of Presenilin and parkin mutants. Presenilin overexpression in the retina produces cell loss, and compromising heparan sulfate biosynthesis rescued retinal patterning and size abnormalities in these animals. parkin is the fly homolog of human PARK2, one of the genes responsible for juvenile onset Parkinson’s Disease. Parkin is involved in mitochondrial surveillance and compromising parkin function results in degeneration of both flight muscle and dopaminergic neurons in Drosophila. Altering heparan sulfate biosynthesis suppressed flight muscle degeneration and mitochondrial dysmorphology, indicating that activation of autophagy-mediated removal of mitochondria (mitophagy) is potentiated in these animals. These findings provide in vivo evidence that altering the levels of heparan sulfate synthesis activates autophagy and can provide protection from a variety of cellular stressors. |
| Databáze: | OpenAIRE |
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