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Shaping the Sperm Head: an ER Enzyme Leaves Its Mark

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Shaping the Sperm Head: an ER Enzyme Leaves Its Mark Shaping the sperm head: an ER enzyme leaves its mark Angshumoy Roy, … , Yi-Nan Lin, Martin M. Matzuk J Clin Invest. 2006;116(11):2860-2863. https://doi.org/10.1172/JCI30221. Commentary Lipid storage diseases are debilitating inherited metabolic disorders that stem from the absence of specific lysosomal enzymes that degrade selected lipids. Most characteristically, these disorders affect the nervous and the reticulo- endothelial systems, with massive organomegaly resulting from the presence of engorged, lipid-laden macrophages. In this issue of the JCI, Yildiz et al. describe the role of the ER-resident enzyme β-glucosidase 2 (GBA2) in mice (see the related article beginning on page 2985). Surprisingly, GBA2 deficiency leaves bile acid and cholesterol metabolism intact, instead causing lipid accumulation in the ER of testicular Sertoli cells, round-headed sperm (globozoospermia), and impaired male fertility. Find the latest version: https://jci.me/30221/pdf commentaries 1. Niederkorn, J.Y. 2006. See no evil, hear no evil, do no 7. Asheuer, M., et al. 2004. Human CD34+ cells dif- 13. Nimmerjahn, A., Kirchhoff, F., and Helmchen, F. evil: the lessons of immune privilege. Nat. Immunol. ferentiate into microglia and express recombinant 2005. Resting microglial cells are highly dynamic 7:354–359. therapeutic protein. Proc. Natl. Acad. Sci. U. S. A. surveillants of brain parenchyma in vivo. Science. 2. Pardridge, W.M. 2005. The blood-brain barrier: 101:3557–3562. 308:1314–1318. bottleneck in brain drug development. NeuroRx. 8. Biffi, A., et al. 2006. Gene therapy of metachromat- 14. Matzner, U., and Gieselmann, V. 2005. Gene thera- 2:3–14. ic leukodystrophy reverses neurological damage py of metachromatic leukodystrophy. Expert Opin. 3. Pardridge, W.M. 2002. Drug and gene delivery to and deficits in mice. J. Clin. Invest. 116:3070–3082. Biol. Ther. 5:55–65. the brain: the vascular route. 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Shaping the sperm head: an ER enzyme leaves its mark Angshumoy Roy,1,2 Yi-Nan Lin,1,3 and Martin M. Matzuk1,2,3 1Department of Pathology, 2Department of Molecular and Human Genetics, and 3Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA. Lipid storage diseases are debilitating inherited metabolic disorders that tion in lysosomes. Patients with Gaucher’s stem from the absence of specific lysosomal enzymes that degrade selected disease commonly exhibit hepatospleno- lipids. Most characteristically, these disorders affect the nervous and the megaly and hematological abnormalities reticulo-endothelial systems, with massive organomegaly resulting from from glucosylceramide accumulation, but the presence of engorged, lipid-laden macrophages. In this issue of the JCI, affected males can sire offspring. Unfortu- Yildiz et al. describe the role of the ER-resident enzyme β-glucosidase 2 nately, Gba-null mice die perinatally (5), pre- (GBA2) in mice (see the related article beginning on page 2985). Surpris- cluding studies on the effects of glucosylce- ingly, GBA2 deficiency leaves bile acid and cholesterol metabolism intact, ramide accumulation on spermatogenesis instead causing lipid accumulation in the ER of testicular Sertoli cells, (Figure 1). Current therapy for Gaucher’s round-headed sperm (globozoospermia), and impaired male fertility. disease involves either recombinant GBA enzyme replacement or administration of Glycosphingolipid metabolism in mamma- monary systems severely affected. Since N-butyldeoxynojirimycin (NB-DNJ; also lian cells is maintained by a group of syn- glycosphingolipids are important in cell known as miglustat), an alkylated imino- thetic and degradative enzymes that often signaling and development, glycosphingo- sugar that reduces glucosylceramide forma- act in different cell types and subcellular lipidoses are often onset in infancy or child- tion by inhibiting UDP-glucose ceramide compartments to achieve homeostasis. The hood and may be fatal if left untreated. glucosyltransferase, the resident Golgi appa- term glycosphingolipidoses refers to a group of ratus enzyme that transfers glucose moieties inherited glycosphingolipid storage disor- Glycolipids do their bit for posterity to ceramide on the cytosolic face of the early ders in humans (reviewed in ref. 1) caused Several classes of glycolipids are essential for Golgi compartment (6) (Figure 1). by mutations in enzymes that degrade spe- spermatogenesis, as demonstrated by sper- In this issue of the JCI, Yildiz et al. (7) show cific lipids in the acidic pH of lysosomes. matogenic failure in mice lacking either sem- that the ER enzyme β-glucosidase 2 (GBA2) Clinically, these disorders present with inolipid or gangliosides (2, 3). Morphologi- is also capable of acting as a glucosylcerami- widespread systemic manifestations, with cally abnormal spermatozoa and impaired dase in vivo in mice — a role hitherto exclu- the nervous, reticulo-endothelial, and pul- fertility are also seen in a mouse model of sively ascribed to its more familiar lysosom- the lipid storage disorder Niemann-Pick dis- al counterpart, GBA. The authors created a Nonstandard abbreviations used: GBA, β-glucosidase ease, with lipid accumulation in testicular mouse line lacking Gba2 and report that bile acid; GBA2, β-glucosidase 2; Gopc, golgi-associated PDZ Sertoli cells (4). In humans, the most com- acid and cholesterol metabolism as well as and coiled motif–containing protein; Hrb, HIV-1 Rev–binding mon glycosphingolipid storage disorder is protein glycosylation in the testes of Gba2- protein; NB-DNJ, N-butyldeoxynojirimycin. Gaucher’s disease (OMIM 230800), which is null mice were minimally affected. However, Conflict of interest: The authors have declared that no conflict of interest exists. caused by mutations in β-glucosidase acid a specific glycolipid — glucosylceramide — Citation for this article: J. Clin. Invest. 116:2860–2863 (GBA; also known as glucosylceramidase) accumulated in Sertoli cells of Gba2-null tes- (2006). doi:10.1172/JCI30221. and results in glucosylceramide accumula- tes. Incidentally, in patients with Gaucher’s 2860 The Journal of Clinical Investigation http://www.jci.org Volume 116 Number 11 November 2006 commentaries Figure 1 Schematic showing subcellular localization and functions of enzymes involved in glucosylceramide metabolism. Top inset: GBA2 hydrolyzes the glucose moiety from glucosylceramides (GlcCer) at the neutral pH of the ER lumen. A nonlysosomal glucosylceramidase (likely GBA2) is inhibited by NB-DNJ. Middle inset: UDP-glucose ceramide glucosyltransferase (UGCG) on the Golgi surface synthesizes glucosylceramide and is inhibited by NB-DNJ. After synthesis, glucosylceramide is flipped back into the Golgi lumen. Bottom inset: Glucosylceramides phagocytosed into the cell are normally degraded in the acidic pH of the lysosome by GBA. The phenotypes of Gba- and Gba2-null mice are described at right. disease, glucosylceramide is also the glyco- NB-DNJ may be due at least in part to its tral question is: How does an ER glucosidase lipid that accumulates within and engorges inhibitory action on GBA2 in the testis. in testicular Sertoli cells affect spermatid hepatic and splenic macrophages (Figure 2). head shape? Yildiz et al. (7) suggest that dis- In contrast to patients with Gaucher’s dis- Shaping the sperm head ruption of germ cell–Sertoli cell glycolipid ease, however, the male (but not the female) Globozoospermia in humans (OMIM transport, with failure of glucosylceramide Gba2-null mice were subfertile, secondary 102530) and mice (Table 1) is a relatively rare breakdown in the Sertoli cell ER of Gba2- to morphological defects of the sperm head defect of
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