title: Oral N-acetyl-cysteine attenuates loss of dopaminergic terminals in alpha-synuclein overexpressing mice.
abstract: Levels of glutathione are lower in the substantia nigra (SN) early in Parkinson's disease (PD) and this may contribute to mitochondrial dysfunction and oxidative stress. Oxidative stress may increase the accumulation of toxic forms of alpha-synuclein (SNCA). We hypothesized that supplementation with n-acetylcysteine (NAC), a source of cysteine--the limiting amino acid in glutathione synthesis, would protect against alpha-synuclein toxicity. Transgenic mice overexpressing wild-type human alpha-synuclein drank water supplemented with NAC or control water supplemented with alanine from ages 6 weeks to 1 year. NAC increased SN levels of glutathione within 5-7 weeks of treatment; however, this increase was not sustained at 1 year. Despite the transient nature of the impact of NAC on brain glutathione, the loss of dopaminergic terminals at 1 year associated with SNCA overexpression was significantly attenuated by NAC supplementation, as measured by immunoreactivity for tyrosine hydroxylase in the striatum (p = 0.007; unpaired, two-tailed t-test), with a similar but nonsignificant trend for dopamine transporter (DAT) immunoreactivity. NAC significantly decreased the levels of human SNCA in the brains of PDGFb-SNCA transgenic mice compared to alanine treated transgenics. This was associated with a decrease in nuclear NFkappaB localization and an increase in cytoplasmic localization of NFkappaB in the NAC-treated transgenics. Overall, these results indicate that oral NAC supplementation decreases SNCA levels in brain and partially protects against loss of dopaminergic terminals associated with overexpression of alpha-synuclein in this model.
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America.
authors.forename: Joanne
authors.initials: J
authors.lastname: Clark
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Clore
authors.forename: Kangni
authors.initials: K
authors.lastname: Zheng
authors.forename: Anthony
authors.initials: A
authors.lastname: Adame
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.forename: David K
authors.initials: DK
authors.lastname: Simon
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage* / Q000494:pharmacology*; D000284:Administration, Oral; D000818:Animals; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D019587:Dietary Supplements; D004298:Dopamine / Q000378:metabolism*; D015870:Gene Expression; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D017072:Neostriatum / Q000187:drug effects* / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D021381:Protein Transport / Q000187:drug effects; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics*
chemical_list: D016328:NF-kappa B; D018696:Neuroprotective Agents; D020574:Proto-Oncogene Proteins c-sis; D051844:alpha-Synuclein; D014446:Tyrosine 3-Monooxygenase; D005978:Glutathione; D004298:Dopamine; D000111:Acetylcysteine
references.citation: Cancer Res. 2004 Aug 1;64(15):5148-53
references.pmid: 15289318
references.citation: Proc Natl Acad Sci U S A. 2007 Aug 21;104(34):13804-9
references.pmid: 17702867
references.citation: Mov Disord. 1994 Jan;9(1):92-7
references.pmid: 8139611
references.citation: Anal Biochem. 1980 Jul 15;106(1):207-12
references.pmid: 7416462
references.citation: Neurochem Int. 2000 Mar;36(3):185-91
references.pmid: 10676851
references.citation: Neurology. 2003 Apr 22;60(8):1234-40
references.pmid: 12707423
references.citation: J Neurosci Methods. 1997 Apr 25;73(1):45-8
references.pmid: 9130677
references.citation: J Cardiovasc Pharmacol. 2004 Jul;44(1):26-34
references.pmid: 15175554
references.citation: Experientia. 1983 Feb 15;39(2):164-5
references.pmid: 6832291
references.citation: Science. 2003 Oct 31;302(5646):841
references.pmid: 14593171
references.citation: Am J Health Syst Pharm. 1999 Jun 1;56(11):1081-91; quiz 1091-3
references.pmid: 10385455
references.citation: Parkinsonism Relat Disord. 2003 Aug;9 Suppl 2:S59-64
references.pmid: 12915069
references.citation: Ann Neurol. 2006 Oct;60(4):389-98
references.pmid: 17068789
references.citation: Lancet. 2004 Sep 25-Oct 1;364(9440):1169-71
references.pmid: 15451225
references.citation: Exp Neurol. 1998 Jan;149(1):109-22
references.pmid: 9454620
references.citation: J Biol Chem. 2000 Jun 16;275(24):18344-9
references.pmid: 10747881
references.citation: Exp Neurol. 2002 May;175(1):35-48
references.pmid: 12009758
references.citation: Neurology. 2001 Oct 23;57(8):1515-7
references.pmid: 11673605
references.citation: Neurology. 1996 Dec;47(6 Suppl 3):S153-60
references.pmid: 8959984
references.citation: J Biol Chem. 2010 Mar 19;285(12):9262-72
references.pmid: 20071342
references.citation: Parkinsonism Relat Disord. 2008;14 Suppl 2:S84-7
references.pmid: 18585084
references.citation: Nat Med. 2002 Jun;8(6):600-6
references.pmid: 12042811
references.citation: Neuroreport. 2000 Aug 3;11(11):2491-3
references.pmid: 10943709
references.citation: Lancet. 2004 Sep 25-Oct 1;364(9440):1167-9
references.pmid: 15451224
references.citation: Neuroreport. 1999 Mar 17;10(4):717-21
references.pmid: 10208537
references.citation: Ann Neurol. 1992;32 Suppl:S116-24
references.pmid: 1510369
references.citation: Eur J Neurosci. 2004 Feb;19(4):845-54
references.pmid: 15009131
references.citation: Neurosci Lett. 1985 Sep 30;60(2):109-14
references.pmid: 3877260
references.citation: Curr Med Chem. 2001 Jun;8(7):809-14
references.pmid: 11375751
references.citation: Ann Neurol. 2003;53 Suppl 3:S26-36; discussion S36-8
references.pmid: 12666096
references.citation: Science. 2000 Feb 18;287(5456):1265-9
references.pmid: 10678833
references.citation: Brain Res. 1997 Jul 11;762(1-2):256-8
references.pmid: 9262186
references.citation: Hum Mol Genet. 2007 Oct 15;16 Spec No. 2:R183-94
references.pmid: 17911161
references.citation: J Neurosci. 2004 Oct 20;24(42):9434-40
references.pmid: 15496679
references.citation: Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18754-9
references.pmid: 18000063
references.citation: Biochem J. 2002 Dec 1;368(Pt 2):545-53
references.pmid: 12180906
references.citation: Cancer Res. 1996 Apr 1;56(7):1642-7
references.pmid: 8603414
references.citation: Science. 2000 Nov 3;290(5493):985-9
references.pmid: 11062131
references.citation: Mol Brain. 2010 Apr 21;3:12
references.pmid: 20409326
references.citation: Hum Mol Genet. 2010 Jan 15;19(2):352-63
references.pmid: 19880420
references.citation: Exp Neurol. 2002 Nov;178(1):80-90
references.pmid: 12460610
references.citation: Mov Disord. 2002 Jul;17(4):645-56
references.pmid: 12210852
references.citation: Exp Neurol. 2010 Mar;222(1):25-9
references.pmid: 19931250
references.citation: J Neurosci. 2002 Apr 1;22(7):2780-91
references.pmid: 11923443
references.citation: Exp Mol Pathol. 2009 Feb;86(1):57-64
references.pmid: 19027004
references.citation: Am J Pathol. 2000 Nov;157(5):1439-45
references.pmid: 11073803
references.citation: Cell Mol Life Sci. 2003 Jan;60(1):6-20
references.pmid: 12613655
references.citation: Res Commun Chem Pathol Pharmacol. 1985 Dec;50(3):435-41
references.pmid: 3878557
references.citation: Brain Res. 2000 Mar 17;859(1):173-5
references.pmid: 10720628
references.citation: Science. 2001 Nov 9;294(5545):1346-9
references.pmid: 11701929
references.citation: J Pharm Pharmacol. 1968 Apr;20(4):302-4
references.pmid: 4384609
references.citation: Life Sci. 1999;64(15):1253-7
references.pmid: 10227580
references.citation: J Neurosci. 2002 Aug 15;22(16):7006-15
references.pmid: 12177198
references.citation: Expert Opin Ther Targets. 2007 Feb;11(2):123-32
references.pmid: 17227229
references.citation: Cell Mol Biol (Noisy-le-grand). 2007 Apr 15;53(1):48-55
references.pmid: 17519111
references.citation: Exp Neurol. 2006 Jun;199(2):249-56
references.pmid: 16310772
references.citation: J Mol Neurosci. 2004;23(1-2):23-34
references.pmid: 15126689
references.citation: Neurosci Lett. 1982 Dec 13;33(3):305-10
references.pmid: 7162692
references.citation: Ann N Y Acad Sci. 2003 Jun;991:171-88
references.pmid: 12846986
references.citation: Biochem Pharmacol. 1966 Oct;15(10):1523-35
references.pmid: 5971807
references.citation: Anal Biochem. 1969 Mar;27(3):502-22
references.pmid: 4388022
references.citation: Nat Neurosci. 2006 Jan;9(1):119-26
references.pmid: 16311588
references.citation: Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2884-9
references.pmid: 12601150
references.citation: Eur J Neurol. 2008 Jan;15(1):1
references.pmid: 18171385
references.citation: J Clin Invest. 1995 Aug;96(2):1169-75
references.pmid: 7635955
references.citation: Biochim Biophys Acta. 1997 Nov 28;1362(1):77-86
references.pmid: 9434102
references.citation: Med Hypotheses. 2001 Apr;56(4):472-7
references.pmid: 11339849
references.citation: J Neurosci. 2001 Oct 15;21(20):8053-61
references.pmid: 11588178
references.citation: Neurosci Lett. 1999 Jan 8;259(2):79-82
references.pmid: 10025562