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Genetic Ablation of Acid Ceramidase in Krabbe Disease Confirms the Psychosine Hypothesis and Identifies a New Therapeutic Target

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Genetic Ablation of Acid Ceramidase in Krabbe Disease Confirms the Psychosine Hypothesis and Identifies a New Therapeutic Target Genetic ablation of acid ceramidase in Krabbe disease confirms the psychosine hypothesis and identifies a new therapeutic target Yedda Lia, Yue Xub, Bruno A. Beniteza, Murtaza S. Nagreec, Joshua T. Dearborna, Xuntian Jianga, Miguel A. Guzmand, Josh C. Woloszynekb, Alex Giaramitab, Bryan K. Yipb, Joseph Elsberndb, Michael C. Babcockb, Melanie Lob, Stephen C. Fowlere, David F. Wozniakf, Carole A. Voglerd, Jeffrey A. Medinc,g, Brett E. Crawfordb, and Mark S. Sandsa,h,1 aDepartment of Medicine, Washington University School of Medicine, St. Louis, MO 63110; bDepartment of Research, BioMarin Pharmaceutical Inc., Novato, CA 94949; cDepartment of Medical Biophysics, University of Toronto, Toronto, ON M5S, Canada; dDepartment of Pathology, St. Louis University School of Medicine, St. Louis, MO 63104; eDepartment of Pharmacology and Toxicology, University of Kansas, Lawrence, KS 66045; fDepartment of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110; gPediatrics and Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226; and hDepartment of Genetics, Washington University School of Medicine, St. Louis, MO 63110 Edited by William S. Sly, Saint Louis University School of Medicine, St. Louis, MO, and approved August 16, 2019 (received for review July 15, 2019) Infantile globoid cell leukodystrophy (GLD, Krabbe disease) is a generated catabolically through the deacylation of galactosylceramide fatal demyelinating disorder caused by a deficiency in the lyso- by acid ceramidase (ACDase). This effectively dissociates GALC somal enzyme galactosylceramidase (GALC). GALC deficiency leads deficiency from psychosine accumulation, allowing us to test the to the accumulation of the cytotoxic glycolipid, galactosylsphingosine long-standing psychosine hypothesis. We demonstrate that genetic (psychosine). Complementary evidence suggested that psychosine loss of ACDase activity [Farber disease (FD) (8)] in the twitcher is synthesized via an anabolic pathway. Here, we show instead that (Twi) (9) model, a GALC-deficient mouse that accurately models psychosine is generated catabolically through the deacylation of Krabbe disease, eliminates psychosine accumulation and cures galactosylceramide by acid ceramidase (ACDase). This reaction GLD. We show that pharmacological inhibition of ACDase ac- uncouples GALC deficiency from psychosine accumulation, allowing tivity with carmofur, an anticancer drug that also inhibits ACD us to test the long-standing “psychosine hypothesis.” We demon- activity (10), significantly decreases psychosine accumulation and MEDICAL SCIENCES strate that genetic loss of ACDase activity (Farber disease) in the prolongs the life span of the twitcher mouse. Previous substrate GALC-deficient mouse model of human GLD (twitcher) eliminates reduction therapy experiments in the twitcher mouse utilized psychosine accumulation and cures GLD. These data suggest that L-cycloserine, which inhibits an enzyme several steps upstream ACDase could be a target for substrate reduction therapy (SRT) in of psychosine synthesis (11, 12). Drugs that directly inhibit Krabbe patients. We show that pharmacological inhibition of ACDase ACDase may have a more acceptable safety profile due to activity with carmofur significantly decreases psychosine accumula- their mechanistic proximity to psychosine biogenesis. In total, tion in cells from a Krabbe patient and prolongs the life span of the these data correctly identify the mechanism of psychosine syn- twitcher (Twi) mouse. Previous SRT experiments in the Twi mouse thesis, clarify the confounding observation of no galactosylcer- utilized L-cycloserine, which inhibits an enzyme several steps up- amide accumulation in Krabbe disease, confirm the long-held stream of psychosine synthesis, thus altering the balance of other important lipids. Drugs that directly inhibit ACDase may have a Significance more acceptable safety profile due to their mechanistic proximity to psychosine biogenesis. In total, these data clarify our understanding This study identifies the source of the toxic glycolipid, of psychosine synthesis, confirm the long-held psychosine hypothesis, galactosylsphingosine (psychosine), which accumulates in the and provide the impetus to discover safe and effective inhibitors of inherited demyelinating disorder, Krabbe disease. It was suggested ACDase to treat Krabbe disease. that psychosine was produced anabolically by the addition of galactose to sphingosine. We show here instead that psychosine is Krabbe disease | acid ceramidase | twitcher mouse | galactosylceramidase | derived from the catabolic deacylation of galactosylceramide by psychosine the lysososomal enzyme acid ceramidase. These findings allow us to test and confirm the ∼45-y-old “psychosine hypothesis,” which nfantile globoid cell leukodystrophy (GLD, Krabbe disease) is states that psychosine causes the pathological and clinical signs of Ian inherited disorder first described in 1916 that is character- Krabbe disease. Finally, these data suggest that acid ceramidase ized by failure to thrive, limb stiffness, seizures, developmental could be a substrate reduction target for treating Krabbe disease. regression, and death by 2–4 y of age (1–3). The disease is caused We show that pharmacological inhibition of acid ceramidase by a deficiency of the lysosomal enzyme galactosylceramidase significantly increases the life span of the twitcher mouse, an (GALC), which is responsible for degrading galactosylceramide, authentic murine model of Krabbe disease. and the cytotoxic glycolipid, galactosylsphingosine (psychosine) (4). In 1972, Miyatake and Suzuki proposed the “psychosine Author contributions: Y.L., Y.X., J.C.W., B.E.C., and M.S.S. designed research; Y.L., B.A.B., hypothesis,” which states that psychosine accumulation is respon- M.S.N., J.T.D., X.J., M.A.G., A.G., B.K.Y., J.E., M.C.B., and M.L. performed research; Y.L., Y.X., S.C.F., and J.A.M. contributed new reagents/analytic tools; Y.L., D.F.W., C.A.V., and sible for the clinical signs associated with Krabbe disease (5). With M.S.S. analyzed data; and Y.L. and M.S.S. wrote the paper. respect to the source of psychosine, complementary evidence Conflict of interest statement: Y.X., J.C.W., A.G., B.K.Y., J.E., M.C.B., M.L., and B.E.C. are suggested that psychosine was synthesized through the anabolic employees of BioMarin Pharmaceutical. The remaining authors declare no conflict addition of galactose to sphingosine (6, 7). Cleland and Kennedy of interest. (1960) showed that labeled galactose was incorporated into psy- This article is a PNAS Direct Submission. chosine in vitro using a crude microsomal fraction from rodent Published under the PNAS license. brain homogenates (6). In 1973, Lin and Radin were unable to 1To whom correspondence may be addressed. Email: [email protected]. demonstrate the existence of a catabolic pathway leading to the This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. production of psychosine, thus indirectly supporting the existence 1073/pnas.1912108116/-/DCSupplemental. of an anabolic mechanism (7). Our data show that psychosine is First published September 16, 2019. www.pnas.org/cgi/doi/10.1073/pnas.1912108116 PNAS | October 1, 2019 | vol. 116 | no. 40 | 20097–20103 Downloaded by guest on September 28, 2021 psychosine hypothesis, and identify acid ceramidase as a poten- ceramide (8). Elevated ceramide levels in liver and spleen, 2 tial therapeutic target for Krabbe disease and possibly other severely affected organs in Farber disease, were observed in FD sphingolipidoses. and Twi/FD mice but not in WT or Twi mice at 36 d (Fig. 2 H and I) or at the terminal time point (SI Appendix, Fig. S2B). Results and Discussion Together, the data presented here strongly suggest that psy- The well-established function of ACDase is to catalyze the chosine is produced primarily through a catabolic mechanism degradation of lysosomal ceramides into sphingosine and fatty (Fig. 1B). In the previously published in vitro experiments di- acids (Fig. 1A). The ceramide that is degraded by ACDase rectly supporting the existence of an anabolic pathway (6), it is originates from several sources, including de novo synthesis of likely that the crude brain homogenates contained an enzyme ceramides, or from degradation products of numerous ceramide (perhaps ceramide galactosyltransferase) that incorporated the derivatives, including glycosphingolipids and sphingomyelins. labeled galactose into galactosylceramide, which was then con- Recently, ACDase was also shown to catalyze the deacylation of verted to psychosine by ACDase. With respect to the prior attempts glucosylceramide to glucosylsphingosine (13, 14). Glucosylcer- to confirm a catabolic mechanism for psychosine production (7), amide and galactosylceramide are stereoisomers. Enzyme–substrate the authors mention in the discussion that they, in fact, detected interactions are typically stereospecific; nevertheless, we hypoth- minute levels of psychosine. Although we show compelling in vitro esized that ACDase can deacylate galactosylceramide to form and in vivo data suggesting that the catabolic pathway is the pri- psychosine (catabolic reaction, Fig. 1B). In a pure in vitro system, mary mechanism for psychosine production, these data do not we showed that recombinant ACDase deacylated an analog of formally exclude the existence of an anabolic pathway. If an an- galactosylceramide to psychosine (Fig. 2A). While ACDase can abolic pathway exists, its contribution is minimal
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