title: Retinoid signaling alterations in amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease for which effective therapeutic interventions and an understanding of underlying disease mechanism are lacking. A variety of biochemical pathways are believed to contribute to the pathophysiology of ALS that are common to both sporadic and familial forms of the disease. Evidence from both human and animal studies indicates that expression of retinoid signaling genes is altered in ALS and may contribute to motor neuron loss. Our goals were to examine the expression and distribution of proteins of the retinoid signaling pathway in spinal cord samples from patients with sporadic and familial ALS and to evaluate the role of these proteins in motor neuron cell survival. In sporadic ALS, the cytoplasmic binding protein that facilitates nuclear translocation of retinoic acid, cellular retinoic acid binding protein-II (CRABP-II), was localized to the nucleus and retinoic acid receptor β (RARβ) was significantly increased in motor neuron nuclei when compared to either familial ALS patients or non-neurologic disease controls. Motor neurons with increased nuclear RARβ were negative for markers of apoptosis. Pre-treatment of primary motor neuron-enriched cultures with a pan-RAR or RARβ-specific agonist decreased motor neuron cell death associated with oxidative injury/stress while a RARβ-specific antagonist enhanced cell death. Our data suggest retinoid signaling is altered in ALS and increased nuclear RARβ occurs in motor neurons of sporadic ALS patients. Activation of RARβ protects motor neurons from oxidative-induced cell death.
authors: Department of Pathology, University of Pittsburgh School of Medicine 200 Lothrop Street, Pittsburgh, PA USA.
authors: Christi L
authors: CL
authors: Kolarcik
authors: Robert
authors: R
authors: Bowser
keywords: Retinoid signaling; amyotrophic lateral sclerosis; motor neuron; motor neurons; nuclear receptor; oxidative stress-induced cell death; retinoic acid receptors
references: J Biol Chem. 2003 Apr 4;278(14):12425-32
references: 12506123
references: Free Radic Biol Med. 2001 May 15;30(10):1067-77
references: 11369496
references: Dev Biol. 1994 Feb;161(2):604-14
references: 8314004
references: Gene. 1999 Jun 24;234(1):87-91
references: 10393242
references: J Neurochem. 2000 Dec;75(6):2511-20
references: 11080204
references: Biochem Biophys Res Commun. 1999 Jul 14;260(3):785-9
references: 10403843
references: Neuron. 2011 Oct 20;72(2):257-68
references: 21944779
references: Mol Cell Biol. 1999 Oct;19(10):7158-67
references: 10490651
references: J Neurosci Methods. 1992 Aug;44(1):59-70
references: 1434751
references: Neurobiol Dis. 2005 Jun-Jul;19(1-2):340-7
references: 15837590
references: Brain Res Brain Res Rev. 2004 Jul;45(3):213-29
references: 15210305
references: J Neuroimmunol. 2002 Jul;128(1-2):31-8
references: 12098508
references: Cell. 2002 Aug 9;110(3):385-97
references: 12176325
references: Nat Neurosci. 1999 Apr;2(4):307-8
references: 10204534
references: J Neuroimmunol. 2005 Feb;159(1-2):146-54
references: 15652414
references: J Neurochem. 2001 Apr;77(1):132-45
references: 11279269
references: Arterioscler Thromb Vasc Biol. 2007 Jul;27(7):1535-41
references: 17478760
references: Physiol Genomics. 2004 Jan 15;16(2):229-39
references: 14645737
references: J Cell Sci. 2002 Oct 1;115(Pt 19):3779-86
references: 12235288
references: Neuroscientist. 2004 Oct;10(5):409-21
references: 15359008
references: J Neurobiol. 2006 Jun;66(7):757-79
references: 16688771
references: Horm Res. 1996;45(3-5):122-7
references: 8964570
references: Neuroscience. 2007 May 25;146(3):1013-9
references: 17418957
references: Mol Hum Reprod. 2001 May;7(5):437-46
references: 11331666
references: Int J Oncol. 2004 Aug;25(2):493-502
references: 15254749
references: J Neurochem. 2005 Dec;95(5):1461-71
references: 16313519
references: J Nutr. 1993 Feb;123(2 Suppl):362-6
references: 8381481
references: J Biol Chem. 1992 Oct 25;267(30):21486-91
references: 1328234
references: Acta Neuropathol. 2004 Jun;107(6):515-22
references: 15024584
references: J Cell Biol. 2007 Apr 9;177(1):73-86
references: 17420291
references: J Neurosci. 1998 Sep 15;18(18):7361-71
references: 9736656
references: Brain Res. 1994 Apr 25;644(1):7-12
references: 8032951
references: J Low Genit Tract Dis. 2001 Jan;5(1):33-7
references: 17043560
references: J Neurochem. 2002 Jan;80(1):158-67
references: 11796754
references: Biosci Rep. 2008 Dec;28(6):327-34
references: 18673301
references: NeuroRx. 2004 Apr;1(2):273-83
references: 15717028
references: J Neurol Sci. 1994 Jul;124 Suppl:73-4
references: 7807150
references: Nat Rev Neurol. 2011 Oct 11;7(11):603-15
references: 21989245
references: Eur J Neurosci. 2006 Jan;23(2):285-95
references: 16420438
references: Eur J Neurosci. 2004 Aug;20(4):896-902
references: 15305858
references: J Neurochem. 2007 Dec;103(5):1821-33
references: 17956549
references: Cell. 1995 Dec 15;83(6):841-50
references: 8521508
references: J Neurooncol. 2007 Sep;84(3):263-7
references: 17453147
references: J Nutr Health Aging. 2004;8(3):156-62
references: 15129301
references: Neuroreport. 2000 Nov 9;11(16):3419-22
references: 11095490
references: J Cell Biol. 1996 Mar;132(5):955-68
references: 8603926
references: Am J Pathol. 2003 Mar;162(3):823-35
references: 12598317
references: J Eur Acad Dermatol Venereol. 2001;15 Suppl 3:5-12
references: 11843234
references: Neurosci Lett. 1998 Apr 24;246(2):93-6
references: 9627188
references: Brain Res Bull. 2007 Mar 15;71(5):437-46
references: 17259011
references: J Lipid Res. 2002 Nov;43(11):1773-808
references: 12401878
references: Trends Biochem Sci. 1992 Oct;17(10):427-33
references: 1333659
references: Muscle Nerve. 2006 Oct;34(4):444-50
references: 16856153
references: J Cell Sci. 2000 Jul;113 ( Pt 14):2567-74
references: 10862714
references: J Neurol Sci. 2003 Mar 15;207(1-2):71-6
references: 12614934
references: Free Radic Biol Med. 2010 Mar 1;48(5):629-41
references: 19969067
references: Neurosci Lett. 2004 Oct 14;369(2):138-41
references: 15450683
references: J Cell Sci. 2002 Dec 15;115(Pt 24):4735-41
references: 12432062
references: J Biol Chem. 1999 Jul 16;274(29):20251-8
references: 10400643
references: Nat Neurosci. 2006 Feb;9(2):243-50
references: 16388307
references: Neurochem Int. 2000 Jan;36(1):1-5
references: 10566953
references: Muscle Nerve. 2010 Jul;42(1):104-11
references: 20583124
references: Ann Neurol. 2005 Feb;57(2):236-51
references: 15668976
references: Mol Cell Neurosci. 2004 Feb;25(2):241-51
references: 15019941
references: J Neurochem. 1997 Apr;68(4):1424-35
references: 9084412
references: EMBO J. 1999 Sep 15;18(18):4903-14
references: 10487743
references: J Biol Chem. 2000 Feb 11;275(6):4145-51
references: 10660575