title: Lysosomal Re-acidification Prevents Lysosphingolipid-Induced Lysosomal Impairment and Cellular Toxicity.
abstract: 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.
authors.affiliation: Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Folts
authors.affiliation: Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America.
authors.forename: Nicole
authors.initials: N
authors.lastname: Scott-Hewitt
authors.affiliation: Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America.
authors.forename: Christoph
authors.initials: C
authors.lastname: Pröschel
authors.affiliation: Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America.
authors.forename: Margot
authors.initials: M
authors.lastname: Mayer-Pröschel
authors.affiliation: Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America.
authors.forename: Mark
authors.initials: M
authors.lastname: Noble
mesh_terms: D000143:Acids / Q000378:metabolism*; D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D004195:Disease Models, Animal; D006801:Humans; D016464:Lysosomal Storage Diseases / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D013107:Sphingolipids / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology
chemical_list: D000143:Acids; D013107:Sphingolipids; D005576:Colforsin