title: Thymic involution and corticosterone level in Sandhoff disease model mice: new aspects the pathogenesis of GM2 gangliosidosis.
abstract: Sandhoff disease (SD) is a lysosomal disease caused by a mutation of the HEXB gene associated with excessive accumulation of GM2 ganglioside (GM2) in lysosomes and neurological manifestations. Production of autoantibodies against the accumulated gangliosides has been reported to be involved in the progressive pathogenesis of GM2 gangliosidosis, although the underlying mechanism has not been fully elucidated. The thymus is the key organ in the acquired immune system including the development of autoantibodies. We showed here that thymic involution and an increase in cell death in the organ occur in SD model mice at a late stage of the pathogenesis. Dramatic increases in the populations of Annexin-V(+) cells and terminal deoxynucletidyl transferase dUTP nick end labeling (TUNEL) (+) cells were observed throughout the thymuses of 15-week old SD mice. Enhanced caspase-3/7 activation, but not that of caspase-1/4, -6 ,-8, or -9, was also demonstrated. Furthermore, the serum level of corticosterone, a potent inducer of apoptosis of thymocytes, was elevated during the same period of apoptosis. Our studies suggested that an increase in endocrine corticosterone may be one of the causes that accelerate the apoptosis of thymocytes leading to thymic involution in GM2 gangliosidosis, and thus can be used as a disease marker for evaluation of the thymic condition and disease progression.
authors: Department of Medicinal Biotechnology, Institute for Medicinal Research, Graduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78 Sho-machi, Tokushima, Tokushima, 770-8505, Japan.
authors: Kazuhiko
authors: K
authors: Matsuoka
authors: Daisuke
authors: D
authors: Tsuji
authors: Takao
authors: T
authors: Taki
authors: Kohji
authors: K
authors: Itoh
references: Genet Med. 2009 Jun;11(6):425-33
references: 19346952
references: Biochim Biophys Acta. 1999 Oct 8;1455(2-3):105-38
references: 10571007
references: J Clin Invest. 2004 Jan;113(2):200-8
references: 14722612
references: Cell Immunol. 1998 Feb 1;183(2):90-8
references: 9606992
references: J Clin Invest. 2009 May;119(5):1241-50
references: 19349688
references: Nat Genet. 1996 Nov;14(3):348-52
references: 8896570
references: J Inherit Metab Dis. 2001;24 Suppl 2:97-105; discussion 87-8
references: 11758685
references: J Biol Chem. 1994 Jun 10;269(23):16276-83
references: 8206933
references: Blood. 2004 Jan 1;103(1):33-9
references: 12969956
references: Curr Opin Immunol. 2008 Jun;20(3):358-68
references: 18501573
references: Brain. 2003 Apr;126(Pt 4):974-87
references: 12615653
references: PLoS One. 2010 Aug 10;5(8):
references: 20856892
references: Trends Endocrinol Metab. 1999 Nov;10(9):353-358
references: 10511694
references: J Clin Invest. 1998 May 1;101(9):1881-8
references: 9576752
references: Vet Immunol Immunopathol. 1998 Jun 12;63(4):335-53
references: 9656423
references: J Exp Med. 2006 Oct 2;203(10):2293-303
references: 16982810
references: Biochem Biophys Res Commun. 2004 Nov 19;324(3):1048-52
references: 15485660
references: Nat Med. 2007 Apr;13(4):439-47
references: 17351625
references: Eur J Immunol. 2001 Aug;31(8):2293-301
references: 11477541
references: J Neurosci. 2007 Dec 12;27(50):13730-8
references: 18077684
references: Beitr Pathol. 1974 Sep;152(4):418-28
references: 4138910
references: Nature. 1994 Nov 3;372(6501):100-3
references: 7969401
references: Proc Natl Acad Sci U S A. 2004 Jun 1;101(22):8425-30
references: 15155903
references: J Exp Med. 1995 Nov 1;182(5):1545-56
references: 7595224
references: J Neurochem. 2009 Nov;111(4):1031-41
references: 19765188
references: Endocrinology. 1999 Dec;140(12):5698-704
references: 10579334
references: Hum Mol Genet. 1997 Oct;6(11):1879-85
references: 9302266
references: Nature. 2005 Mar 24;434(7032):520-5
references: 15791257