title: Amino acid analog toxicity in primary rat neuronal and astrocyte cultures: implications for protein misfolding and TDP-43 regulation.
abstract: Amino acid analogs promote translational errors that result in aberrant protein synthesis and have been used to understand the effects of protein misfolding in a variety of physiological and pathological settings. TDP-43 is a protein that is linked to protein aggregation and toxicity in a variety of neurodegenerative diseases. This study exposed primary rat neurons and astrocyte cultures to established amino acid analogs (canavanine and azetidine-2-carboxylic acid) and showed that both cell types undergo a dose-dependent increase in toxicity, with neurons exhibiting a greater degree of toxicity compared with astrocytes. Neurons and astrocytes exhibited similar increases in ubiquitinated and oxidized protein following analog treatment. Analog treatment increased heat shock protein (Hsp) levels in both neurons and astrocytes. In neurons, and to a lesser extent astrocytes, the levels of TDP-43 increased in response to analog treatment. Taken together, these data indicate that neurons exhibit preferential toxicity and alterations in TDP-43 in response to increased protein misfolding compared with astrocytes.
authors: Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808-4124, USA.
authors: Kalavathi
authors: K
authors: Dasuri
authors: Philip J
authors: PJ
authors: Ebenezer
authors: Romina M
authors: RM
authors: Uranga
authors: Elena
authors: E
authors: Gavilán
authors: Le
authors: L
authors: Zhang
authors: Sun O K
authors: SO
authors: Fernandez-Kim
authors: Annadora J
authors: AJ
authors: Bruce-Keller
authors: Jeffrey N
authors: JN
authors: Keller
references: Mol Cell Biol. 1984 Jun;4(6):1063-72
references: 6610822
references: J Biol Chem. 1975 Feb 10;250(3):1112-22
references: 1089651
references: J Neurochem. 2006 Jan;96(1):1-13
references: 16305625
references: Mol Cell Biol. 1988 Jan;8(1):393-405
references: 3275876
references: Biochim Biophys Acta. 1975 Oct 9;404(2):180-7
references: 1101962
references: J Alzheimers Dis. 2010;22(3):839-48
references: 20858948
references: J Neurosci Res. 1999 Dec 15;58(6):823-30
references: 10583913
references: Neurotox Res. 2002 Feb;4(1):1-13
references: 12826488
references: J Neurosci. 2010 Jun 2;30(22):7729-39
references: 20519548
references: J Neurosci. 2010 Jan 13;30(2):639-49
references: 20071528
references: J Biol Chem. 1998 Feb 6;273(6):3180-91
references: 9452429
references: Biochem Biophys Res Commun. 2006 Dec 22;351(3):602-11
references: 17084815
references: Science. 1986 Apr 25;232(4749):522-4
references: 3083508
references: Nature. 1988 Mar 31;332(6163):462-4
references: 3352747
references: J Neurosci Res. 2005 Jun 1;80(5):655-66
references: 15880562
references: Nat Genet. 2008 May;40(5):572-4
references: 18372902
references: Cell. 1991 Jul 26;66(2):191-7
references: 1855252
references: Mol Neurobiol. 2005;31(1-3):205-17
references: 15953822
references: Mol Cell. 2006 Jun 23;22(6):713-717
references: 16793541
references: J Cell Physiol. 1980 Mar;102(3):407-27
references: 6901532
references: Trends Neurosci. 2007 Jan;30(1):31-6
references: 17126920
references: Cell. 1978 Dec;15(4):1277-86
references: 569556
references: J Neurosci. 1997 Jul 1;17(13):5089-100
references: 9185546
references: J Cell Physiol. 1985 Jan;122(1):91-7
references: 3965486
references: Nat Rev Neurol. 2010 Apr;6(4):211-20
references: 20234357
references: J Biol Chem. 2010 Aug 27;285(35):27385-27395
references: 20605781
references: Mol Biol Cell. 2004 Feb;15(2):637-48
references: 14617820
references: Proc Natl Acad Sci U S A. 1999 Aug 31;96(18):9989-90
references: 10468546
references: J Biol Chem. 2009 Dec 4;284(49):33713-8
references: 19812037
references: Free Radic Biol Med. 2010 Nov 1;49(8):1290-7
references: 20678570
references: Phytochemistry. 2010 Apr;71(5-6):502-7
references: 20064647
references: FASEB J. 2006 Jun;20(8):1055-63
references: 16770004
references: Ann N Y Acad Sci. 2005 Dec;1066:181-221
references: 16533927
references: Free Radic Biol Med. 2010 May 15;48(10):1330-7
references: 20188163
references: Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7313-8
references: 11416208
references: Adv Enzymol Relat Areas Mol Biol. 1967;29:89-163
references: 4881886
references: J Neurosci. 1998 Jan 15;18(2):687-97
references: 9425011
references: Neurodegener Dis. 2010;7(4):260-4
references: 20197650
references: Neuropathol Appl Neurobiol. 2004 Jun;30(3):215-24
references: 15175075
references: Biopolymers. 1990;30(9-10):951-9
references: 2092823
references: Curr Protein Pept Sci. 2008 Oct;9(5):507-40
references: 18855701
references: Int J Biochem Cell Biol. 2008;40(8):1452-66
references: 18329946
references: Annu Rev Biochem. 1974;43(0):835-69
references: 4604628
references: J Cell Sci. 2004 Jan 15;117(Pt 2):281-92
references: 14657277
references: Annu Rev Biochem. 1992;61:761-807
references: 1323239
references: Curr Opin Cell Biol. 1992 Dec;4(6):1024-31
references: 1336669
references: Nat Med. 2004 Jul;10 Suppl:S10-7
references: 15272267
references: J Biol Chem. 2002 Nov 22;277(47):44817-25
references: 12239211
references: Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11505-10
references: 14500784
references: J Neurosci Res. 2004 Nov 1;78(3):420-9
references: 15389841
references: J Biol Chem. 1989 Aug 15;264(23):13693-6
references: 2760038
references: Science. 2006 Oct 6;314(5796):130-3
references: 17023659
references: Proc Natl Acad Sci U S A. 2009 May 5;106(18):7607-12
references: 19383787
references: Neurosci Lett. 2010 Jul 5;478(2):72-6
references: 20447446