Insufficient ER-stress response causes selective mouse cerebellar granule cell degeneration resembling that seen in congenital disorders of glycosylation
Tóm tắt
Congenital disorders of glycosylation (CDGs) are inherited diseases caused by glycosylation defects. Incorrectly glycosylated proteins induce protein misfolding and endoplasmic reticulum (ER) stress. The most common form of CDG, PMM2-CDG, is caused by deficiency in the cytosolic enzyme phosphomannomutase 2 (PMM2). Patients with PMM2-CDG exhibit a significantly reduced number of cerebellar Purkinje cells and granule cells. The molecular mechanism underlying the specific cerebellar neurodegeneration in PMM2-CDG, however, remains elusive. Herein, we report that cerebellar granule cells (CGCs) are more sensitive to tunicamycin (TM)-induced inhibition of total N-glycan synthesis than cortical neurons (CNs). When glycan synthesis was inhibited to a comparable degree, CGCs exhibited more cell death than CNs. Furthermore, downregulation of PMM2 caused more CGCs to die than CNs. Importantly, we found that upon PMM2 downregulation or TM treatment, ER-stress response proteins were elevated less significantly in CGCs than in CNs, with the GRP78/BiP level showing the most significant difference. We further demonstrate that overexpression of GRP78/BiP rescues the death of CGCs resulting from either TM-treatment or PMM2 downregulation. Our results indicate that the selective susceptibility of cerebellar neurons to N-glycosylation defects is due to these neurons’ inefficient response to ER stress, providing important insight into the mechanisms of selective neurodegeneration observed in CDG patients.
Tài liệu tham khảo
Freeze HH: Congenital disorders of glycosylation: CDG-I, CDG-II, and beyond. Curr Mol Med. 2007, 7: 389-396. 10.2174/156652407780831548.
Marquardt T, Denecke J: Congenital disorders of glycosylation: review of their molecular bases, clinical presentations and specific therapies. Eur J Pediatr. 2003, 162: 359-379.
Aronica E, van Kempen AA, van der Heide M, Poll-The BT, van Slooten HJ, Troost D, Rozemuller-Kwakkel JM: Congenital disorder of glycosylation type Ia: a clinicopathological report of a newborn infant with cerebellar pathology. Acta Neuropathol. 2005, 109: 433-442. 10.1007/s00401-004-0975-3.
Schoffer KL, O’Sullivan JD, McGill J: Congenital disorder of glycosylation type Ia presenting as early-onset cerebellar ataxia in an adult. Mov Disord. 2006, 21: 869-872. 10.1002/mds.20804.
Bergmann AK, Campagna DR, McLoughlin EM, Agarwal S, Fleming MD, Bottomley SS, Neufeld EJ: Systematic molecular genetic analysis of congenital sideroblastic anemia: evidence for genetic heterogeneity and identification of novel mutations. Pediatr Blood Cancer. 2010, 54: 273-278.
Zhao L, Ackerman SL: Endoplasmic reticulum stress in health and disease. Curr Opin Cell Biol. 2006, 18: 444-452. 10.1016/j.ceb.2006.06.005.
Saura CA, Choi SY, Beglopoulos V, Malkani S, Zhang D, Shankaranarayana Rao BS, Chattarji S, Kelleher RJ, Kandel ER, Duff K, et al: Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration. Neuron. 2004, 42: 23-36. 10.1016/S0896-6273(04)00182-5.
Jiang P, Gan M, Ebrahim AS, Lin WL, Melrose HL, Yen SH: ER stress response plays an important role in aggregation of alpha-synuclein. Mol Neurodegener. 2010, 5: 56-10.1186/1750-1326-5-56.
Travers KJ, Patil CK, Wodicka L, Lockhart DJ, Weissman JS, Walter P: Functional and genomic analyses reveal an essential coordination between the unfolded protein response and ER-associated degradation. Cell. 2000, 101: 249-258. 10.1016/S0092-8674(00)80835-1.
Zhang K, Kaufman RJ: The unfolded protein response: a stress signaling pathway critical for health and disease. Neurology. 2006, 66: S102-109. 10.1212/01.wnl.0000192306.98198.ec.
Ron D, Walter P: Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol. 2007, 8: 519-529. 10.1038/nrm2199.
Lecca MR, Wagner U, Patrignani A, Berger EG, Hennet T: Genome-wide analysis of the unfolded protein response in fibroblasts from congenital disorders of glycosylation type-I patients. FASEB J. 2005, 19: 240-242.
Tkacz JS, Lampen O: Tunicamycin inhibition of polyisoprenyl N-acetylglucosaminyl pyrophosphate formation in calf-liver microsomes. Biochem Biophys Res Commun. 1975, 65: 248-257. 10.1016/S0006-291X(75)80086-6.
Elbein AD: Inhibitors of the biosynthesis and processing of N-linked oligosaccharide chains. Annu Rev Biochem. 1987, 56: 497-534. 10.1146/annurev.bi.56.070187.002433.
Suzuki T, Funakoshi Y: Free N-linked oligosaccharide chains: formation and degradation. Glycoconj J. 2006, 23: 291-302. 10.1007/s10719-006-6975-x.
Caramelo JJ, Parodi AJ: How sugars convey information on protein conformation in the endoplasmic reticulum. Semin Cell Dev Biol. 2007, 18: 732-742. 10.1016/j.semcdb.2007.09.006.
Willem M, Garratt AN, Novak B, Citron M, Kaufmann S, Rittger A, DeStrooper B, Saftig P, Birchmeier C, Haass C: Control of peripheral nerve myelination by the beta-secretase BACE1. Science. 2006, 314: 664-666. 10.1126/science.1132341.
Raben D, Helfrich B, Chan DC, Ciardiello F, Zhao L, Franklin W, Baron AE, Zeng C, Johnson TK, Bunn PA: The effects of cetuximab alone and in combination with radiation and/or chemotherapy in lung cancer. Clin Cancer Res. 2005, 11: 795-805.
Kimata Y, Kimata YI, Shimizu Y, Abe H, Farcasanu IC, Takeuchi M, Rose MD, Kohno K: Genetic evidence for a role of BiP/Kar2 that regulates Ire1 in response to accumulation of unfolded proteins. Mol Biol Cell. 2003, 14: 2559-2569. 10.1091/mbc.E02-11-0708.
Schollen E, Pardon E, Heykants L, Renard J, Doggett NA, Callen DF, Cassiman JJ, Matthijs G: Comparative analysis of the phosphomannomutase genes PMM1, PMM2 and PMM2psi: the sequence variation in the processed pseudogene is a reflection of the mutations found in the functional gene. Hum Mol Genet. 1998, 7: 157-164. 10.1093/hmg/7.2.157.
Matthijs G, Schollen E, Pirard M, Budarf ML, Van Schaftingen E, Cassiman JJ: PMM (PMM1), the human homologue of SEC53 or yeast phosphomannomutase, is localized on chromosome 22q13. Genomics. 1997, 40: 41-47. 10.1006/geno.1996.4536.
Cromphout K, Vleugels W, Heykants L, Schollen E, Keldermans L, Sciot R, D’Hooge R, De Deyn PP, von Figura K, Hartmann D, et al: The normal phenotype of Pmm1-deficient mice suggests that Pmm1 is not essential for normal mouse development. Mol Cell Biol. 2006, 26: 5621-5635. 10.1128/MCB.02357-05.
Thiel C, Lubke T, Matthijs G, von Figura K, Korner C: Targeted disruption of the mouse phosphomannomutase 2 gene causes early embryonic lethality. Mol Cell Biol. 2006, 26: 5615-5620. 10.1128/MCB.02391-05.
Volbracht C, Leist M, Nicotera P: ATP controls neuronal apoptosis triggered by microtubule breakdown or potassium deprivation. Mol Med. 1999, 5: 477-489.
Kwak YD, Wang R, Li JJ, Zhang YW, Xu H, Liao FF: Differential regulation of BACE1 expression by oxidative and nitrosative signals. Mol Neurodegener. 2011, 6: 17-10.1186/1750-1326-6-17.
Sun L, Eklund EA, Chung WK, Wang C, Cohen J, Freeze HH: Congenital disorder of glycosylation id presenting with hyperinsulinemic hypoglycemia and islet cell hyperplasia. J Clin Endocrinol Metab. 2005, 90: 4371-4375. 10.1210/jc.2005-0250.
Van Schaftingen E, Jaeken J: Phosphomannomutase deficiency is a cause of carbohydrate-deficient glycoprotein syndrome type I. FEBS Lett. 1995, 377: 318-320. 10.1016/0014-5793(95)01357-1.