Oral N-acetyl-cysteine attenuates loss of dopaminergic terminals in alpha-synuclein overexpressing mice.
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.
Clark
Joanne
J
Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America.
Clore
Elizabeth L
EL
Zheng
Kangni
K
Adame
Anthony
A
Masliah
Eliezer
E
Simon
David K
DK
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*
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
Cancer Res. 2004 Aug 1;64(15):5148-53
15289318
Proc Natl Acad Sci U S A. 2007 Aug 21;104(34):13804-9
17702867
Mov Disord. 1994 Jan;9(1):92-7
8139611
Anal Biochem. 1980 Jul 15;106(1):207-12
7416462
Neurochem Int. 2000 Mar;36(3):185-91
10676851
Neurology. 2003 Apr 22;60(8):1234-40
12707423
J Neurosci Methods. 1997 Apr 25;73(1):45-8
9130677
J Cardiovasc Pharmacol. 2004 Jul;44(1):26-34
15175554
Experientia. 1983 Feb 15;39(2):164-5
6832291
Science. 2003 Oct 31;302(5646):841
14593171
Am J Health Syst Pharm. 1999 Jun 1;56(11):1081-91; quiz 1091-3
10385455
Parkinsonism Relat Disord. 2003 Aug;9 Suppl 2:S59-64
12915069
Ann Neurol. 2006 Oct;60(4):389-98
17068789
Lancet. 2004 Sep 25-Oct 1;364(9440):1169-71
15451225
Exp Neurol. 1998 Jan;149(1):109-22
9454620
J Biol Chem. 2000 Jun 16;275(24):18344-9
10747881
Exp Neurol. 2002 May;175(1):35-48
12009758
Neurology. 2001 Oct 23;57(8):1515-7
11673605
Neurology. 1996 Dec;47(6 Suppl 3):S153-60
8959984
J Biol Chem. 2010 Mar 19;285(12):9262-72
20071342
Parkinsonism Relat Disord. 2008;14 Suppl 2:S84-7
18585084
Nat Med. 2002 Jun;8(6):600-6
12042811
Neuroreport. 2000 Aug 3;11(11):2491-3
10943709
Lancet. 2004 Sep 25-Oct 1;364(9440):1167-9
15451224
Neuroreport. 1999 Mar 17;10(4):717-21
10208537
Ann Neurol. 1992;32 Suppl:S116-24
1510369
Eur J Neurosci. 2004 Feb;19(4):845-54
15009131
Neurosci Lett. 1985 Sep 30;60(2):109-14
3877260
Curr Med Chem. 2001 Jun;8(7):809-14
11375751
Ann Neurol. 2003;53 Suppl 3:S26-36; discussion S36-8
12666096
Science. 2000 Feb 18;287(5456):1265-9
10678833
Brain Res. 1997 Jul 11;762(1-2):256-8
9262186
Hum Mol Genet. 2007 Oct 15;16 Spec No. 2:R183-94
17911161
J Neurosci. 2004 Oct 20;24(42):9434-40
15496679
Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18754-9
18000063
Biochem J. 2002 Dec 1;368(Pt 2):545-53
12180906
Cancer Res. 1996 Apr 1;56(7):1642-7
8603414
Science. 2000 Nov 3;290(5493):985-9
11062131
Mol Brain. 2010 Apr 21;3:12
20409326
Hum Mol Genet. 2010 Jan 15;19(2):352-63
19880420
Exp Neurol. 2002 Nov;178(1):80-90
12460610
Mov Disord. 2002 Jul;17(4):645-56
12210852
Exp Neurol. 2010 Mar;222(1):25-9
19931250
J Neurosci. 2002 Apr 1;22(7):2780-91
11923443
Exp Mol Pathol. 2009 Feb;86(1):57-64
19027004
Am J Pathol. 2000 Nov;157(5):1439-45
11073803
Cell Mol Life Sci. 2003 Jan;60(1):6-20
12613655
Res Commun Chem Pathol Pharmacol. 1985 Dec;50(3):435-41
3878557
Brain Res. 2000 Mar 17;859(1):173-5
10720628
Science. 2001 Nov 9;294(5545):1346-9
11701929
J Pharm Pharmacol. 1968 Apr;20(4):302-4
4384609
Life Sci. 1999;64(15):1253-7
10227580
J Neurosci. 2002 Aug 15;22(16):7006-15
12177198
Expert Opin Ther Targets. 2007 Feb;11(2):123-32
17227229
Cell Mol Biol (Noisy-le-grand). 2007 Apr 15;53(1):48-55
17519111
Exp Neurol. 2006 Jun;199(2):249-56
16310772
J Mol Neurosci. 2004;23(1-2):23-34
15126689
Neurosci Lett. 1982 Dec 13;33(3):305-10
7162692
Ann N Y Acad Sci. 2003 Jun;991:171-88
12846986
Biochem Pharmacol. 1966 Oct;15(10):1523-35
5971807
Anal Biochem. 1969 Mar;27(3):502-22
4388022
Nat Neurosci. 2006 Jan;9(1):119-26
16311588
Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2884-9
12601150
Eur J Neurol. 2008 Jan;15(1):1
18171385
J Clin Invest. 1995 Aug;96(2):1169-75
7635955
Biochim Biophys Acta. 1997 Nov 28;1362(1):77-86
9434102
Med Hypotheses. 2001 Apr;56(4):472-7
11339849
J Neurosci. 2001 Oct 15;21(20):8053-61
11588178
Neurosci Lett. 1999 Jan 8;259(2):79-82
10025562