Reducing GBA2 Activity Ameliorates Neuropathology in Niemann-Pick Type C Mice

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2015 Aug 15

PMID 26275242

Citations 31

Authors

Andre R A Marques

Jan Aten

Roelof Ottenhoff

Cindy P A A van Roomen

Daniela Herrera Moro

Nike Claessen

Maria Fernanda Vinueza Veloz

Kuikui Zhou

Zhanmin Lin

Mina Mirzaian

Rolf G Boot

Chris I De Zeeuw

Herman S Overkleeft

Yildiz Yildiz

Johannes M F G Aerts

Affiliations

Soon will be listed here.

Abstract

The enzyme glucocerebrosidase (GBA) hydrolyses glucosylceramide (GlcCer) in lysosomes. Markedly reduced GBA activity is associated with severe manifestations of Gaucher disease including neurological involvement. Mutations in the GBA gene have recently also been identified as major genetic risk factor for Parkinsonism. Disturbed metabolism of GlcCer may therefore play a role in neuropathology. Besides lysosomal GBA, cells also contain a non-lysosomal glucosylceramidase (GBA2). Given that the two β-glucosidases share substrates, we speculated that over-activity of GBA2 during severe GBA impairment might influence neuropathology. This hypothesis was studied in Niemann-Pick type C (Npc1-/-) mice showing secondary deficiency in GBA in various tissues. Here we report that GBA2 activity is indeed increased in the brain of Npc1-/- mice. We found that GBA2 is particularly abundant in Purkinje cells (PCs), one of the most affected neuronal populations in NPC disease. Inhibiting GBA2 in Npc1-/- mice with a brain-permeable low nanomolar inhibitor significantly improved motor coordination and extended lifespan in the absence of correction in cholesterol and ganglioside abnormalities. This trend was recapitulated, although not to full extent, by introducing a genetic loss of GBA2 in Npc1-/- mice. Our findings point to GBA2 activity as therapeutic target in NPC.

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References

Korschen H, Yildiz Y, Raju D, Schonauer S, Bonigk W, Jansen V . The non-lysosomal β-glucosidase GBA2 is a non-integral membrane-associated protein at the endoplasmic reticulum (ER) and Golgi. J Biol Chem. 2012; 288(5):3381-93. PMC: 3561557. DOI: 10.1074/jbc.M112.414714. View

Sarkar S, Carroll B, Buganim Y, Maetzel D, Ng A, Cassady J . Impaired autophagy in the lipid-storage disorder Niemann-Pick type C1 disease. Cell Rep. 2013; 5(5):1302-15. PMC: 3957429. DOI: 10.1016/j.celrep.2013.10.042. View

Zervas M, Somers K, Thrall M, Walkley S . Critical role for glycosphingolipids in Niemann-Pick disease type C. Curr Biol. 2001; 11(16):1283-7. DOI: 10.1016/s0960-9822(01)00396-7. View

Kallemeijn W, Li K, Witte M, Marques A, Aten J, Scheij S . Novel activity-based probes for broad-spectrum profiling of retaining β-exoglucosidases in situ and in vivo. Angew Chem Int Ed Engl. 2012; 51(50):12529-33. DOI: 10.1002/anie.201207771. View

Van Weely S, Brandsma M, Strijland A, Tager J, Aerts J . Demonstration of the existence of a second, non-lysosomal glucocerebrosidase that is not deficient in Gaucher disease. Biochim Biophys Acta. 1993; 1181(1):55-62. DOI: 10.1016/0925-4439(93)90090-n. View

Yildiz Y, Hoffmann P, Vom Dahl S, Breiden B, Sandhoff R, Niederau C . Functional and genetic characterization of the non-lysosomal glucosylceramidase 2 as a modifier for Gaucher disease. Orphanet J Rare Dis. 2013; 8:151. PMC: 3850879. DOI: 10.1186/1750-1172-8-151. View

Overkleeft H, Renkema G, Neele J, Vianello P, Hung I, Strijland A . Generation of specific deoxynojirimycin-type inhibitors of the non-lysosomal glucosylceramidase. J Biol Chem. 1998; 273(41):26522-7. DOI: 10.1074/jbc.273.41.26522. View

der Vlugt K, Langeveld M, Poppema A, Kuiper S, Hollak C, Aerts J . Prominent increase in plasma ganglioside GM3 is associated with clinical manifestations of type I Gaucher disease. Clin Chim Acta. 2008; 389(1-2):109-13. DOI: 10.1016/j.cca.2007.12.001. View

Groener J, Poorthuis B, Kuiper S, Helmond M, Hollak C, Aerts J . HPLC for simultaneous quantification of total ceramide, glucosylceramide, and ceramide trihexoside concentrations in plasma. Clin Chem. 2007; 53(4):742-7. DOI: 10.1373/clinchem.2006.079012. View

10.

Burke D, Rahim A, Waddington S, Karlsson S, Enquist I, Bhatia K . Increased glucocerebrosidase (GBA) 2 activity in GBA1 deficient mice brains and in Gaucher leucocytes. J Inherit Metab Dis. 2012; 36(5):869-72. DOI: 10.1007/s10545-012-9561-3. View

11.

Pentchev P, GAL A, Booth A, Omodeo-Sale F, Fouks J, Neumeyer B . A lysosomal storage disorder in mice characterized by a dual deficiency of sphingomyelinase and glucocerebrosidase. Biochim Biophys Acta. 1980; 619(3):669-79. DOI: 10.1016/0005-2760(80)90116-2. View

12.

BLIGH E, Dyer W . A rapid method of total lipid extraction and purification. Can J Biochem Physiol. 1959; 37(8):911-7. DOI: 10.1139/o59-099. View

13.

Dekker N, van Dussen L, Hollak C, Overkleeft H, Scheij S, Ghauharali K . Elevated plasma glucosylsphingosine in Gaucher disease: relation to phenotype, storage cell markers, and therapeutic response. Blood. 2011; 118(16):e118-27. PMC: 3685900. DOI: 10.1182/blood-2011-05-352971. View

14.

Elleder M . Glucosylceramide transfer from lysosomes--the missing link in molecular pathology of glucosylceramidase deficiency: a hypothesis based on existing data. J Inherit Metab Dis. 2006; 29(6):707-15. DOI: 10.1007/s10545-006-0411-z. View

15.

Yildiz Y, Matern H, Thompson B, Allegood J, Warren R, Ramirez D . Mutation of beta-glucosidase 2 causes glycolipid storage disease and impaired male fertility. J Clin Invest. 2006; 116(11):2985-94. PMC: 1626112. DOI: 10.1172/JCI29224. View

16.

Sleat D, Wiseman J, El-Banna M, Price S, Verot L, Shen M . Genetic evidence for nonredundant functional cooperativity between NPC1 and NPC2 in lipid transport. Proc Natl Acad Sci U S A. 2004; 101(16):5886-91. PMC: 395893. DOI: 10.1073/pnas.0308456101. View

17.

Nalls M, Duran R, Lopez G, Kurzawa-Akanbi M, McKeith I, Chinnery P . A multicenter study of glucocerebrosidase mutations in dementia with Lewy bodies. JAMA Neurol. 2013; 70(6):727-35. PMC: 3841974. DOI: 10.1001/jamaneurol.2013.1925. View

18.

Vanier M . Niemann-Pick disease type C. Orphanet J Rare Dis. 2010; 5:16. PMC: 2902432. DOI: 10.1186/1750-1172-5-16. View

19.

Ashe K, Bangari D, Li L, Cabrera-Salazar M, Bercury S, Nietupski J . Iminosugar-based inhibitors of glucosylceramide synthase increase brain glycosphingolipids and survival in a mouse model of Sandhoff disease. PLoS One. 2011; 6(6):e21758. PMC: 3126858. DOI: 10.1371/journal.pone.0021758. View

20.

van der Giessen R, Koekkoek S, van Dorp S, De Gruijl J, Cupido A, Khosrovani S . Role of olivary electrical coupling in cerebellar motor learning. Neuron. 2008; 58(4):599-612. DOI: 10.1016/j.neuron.2008.03.016. View