Lysosomal Re-acidification Prevents Lysosphingolipid-Induced Lysosomal Impairment and Cellular Toxicity

Autor: Nicole Scott-Hewitt, Margot Mayer-Pröschel, Christoph Pröschel, Mark Noble, Christopher J. Folts
Jazyk: angličtina
Rok vydání: 2016
Předmět:
0301 basic medicine
Toxicology
Pathology and Laboratory Medicine
Biochemistry
Mechanical Treatment of Specimens
Infographics
Mice
Myelin
Medicine and Health Sciences
Cell Cycle and Cell Division
Biology (General)
Cell Disruption
Stem Cells
General Neuroscience
Animal Models
Lipids
3. Good health
Cell biology
medicine.anatomical_structure
Specimen Disruption
Cell Processes
Protective Agents
Toxicity
Cellular Structures and Organelles
Stem cell
General Agricultural and Biological Sciences
Graphs
Research Article
Computer and Information Sciences
QH301-705.5
Toxic Agents
Central nervous system
Mouse Models
Biology
Research and Analysis Methods
General Biochemistry
Genetics and Molecular Biology
03 medical and health sciences
Model Organisms
medicine
Animals
Humans
Sphingolipids
General Immunology and Microbiology
Data Visualization
Colforsin
Biology and Life Sciences
Cell Biology
medicine.disease
Sphingolipid
Oligodendrocyte
Lysosomal Storage Diseases
Disease Models
Animal
030104 developmental biology
Specimen Preparation and Treatment
Krabbe disease
Lysosomes
Acids
Zdroj: PLoS Biology, Vol 14, Iss 12, p e1002583 (2016)
PLoS Biology
ISSN: 1545-7885
1544-9173
Popis: Neurodegenerative lysosomal storage disorders (LSDs) are severe and untreatable, and mechanisms underlying cellular dysfunction are poorly understood. We found that toxic lipids relevant to three different LSDs disrupt multiple lysosomal and other cellular functions. Unbiased drug discovery revealed several structurally distinct protective compounds, approved for other uses, that prevent lysosomal and cellular toxicities of these lipids. Toxic lipids and protective agents show unexpected convergence on control of lysosomal pH and re-acidification as a critical component of toxicity and protection. In twitcher mice (a model of Krabbe disease [KD]), a central nervous system (CNS)-penetrant protective agent rescued myelin and oligodendrocyte (OL) progenitors, improved motor behavior, and extended lifespan. Our studies reveal shared principles relevant to several LSDs, in which diverse cellular and biochemical disruptions appear to be secondary to disruption of lysosomal pH regulation by specific lipids. These studies also provide novel protective strategies that confer therapeutic benefits in a mouse model of a severe LSD.
Different structurally related lipids from three genetically distinct lysosomal storage disorders are sufficient to cause multiple dysfunctions that converge on disruption of lysosomal pH as a core pathogenic mechanism.
Author Summary Neurodegenerative lysosomal storage disorders (LSDs) are severe and untreatable recessive genetic disorders that cause devastating damage to the nervous system. These diseases exhibit severe disruption of lysosomes (a cellular organelle that breaks down lipids and proteins) and other aspects of cell function. However, the means by which mutations cause these dysfunctions are poorly understood. By studying different lipids that accumulate in three different LSDs, we found that lipids with specific shared structures are sufficient to cause multiple lysosomal and cellular dysfunctions, including an abnormal alkalization of the lysosomal pH. We prevented all of these dysfunctions by promoting lysosomal re-acidification and discovered several drugs—already approved for other purposes—with unexpected abilities to restore lysosomal pH and rescue cells. In a genetic mouse model of a severe LSD, one of these compounds decreased tissue damage, improved quality of life, and extended survival. In contrast with previous studies on individual disorders, our study provides novel shared principles relevant to several LSDs and uncovers relevant compounds able to provide multiple benefits in a disease-relevant model in vivo.
Databáze: OpenAIRE
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