title: Sustained resistance to acute MPTP toxicity by hypothalamic dopamine neurons following chronic neurotoxicant exposure is associated with sustained up-regulation of parkin protein.
abstract: Hypothalamic tuberoinfundibular dopamine (TIDA) neurons remain unaffected in Parkinson disease (PD) while there is significant degeneration of midbrain nigrostriatal dopamine (NSDA) neurons. A similar pattern of susceptibility is observed following acute exposure to the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and the resistance of TIDA neurons to MPTP is associated with increased expression of parkin and ubiquitin carboxy-terminal hydrolase L-1 (UCHL-1). In the present study, the response of TIDA and NSDA neurons to acute MPTP administration following chronic MPTP exposure was examined. Mice were treated with ten injections of either MPTP (20mg/kg; s.c.; every 3.5 days) or saline vehicle (10 ml/kg; s.c.; every 3.5 days). Following a 21 day recovery period, chronic saline- and MPTP-treated mice received an additional injection of either saline (10 ml/kg; s.c.) or MPTP (20mg/kg; s.c.) and were sacrificed 24h later. NSDA neurons displayed significant axon terminal degeneration (as reflected by decreases in DA, tyrosine hydroxylase (TH) and DA transporter concentrations in the striatum) as well as loss of TH-immunoreactive (IR) neurons in the substantia nigra (SN) following MPTP, whereas TIDA neurons revealed no overt axon terminal pathology or loss of TH-IR cell bodies. NSDA neuronal pathology was associated with transient decreases in concentrations of parkin and UCHL-1 protein in the SN, which returned to normal levels by 21 days following cessation of chronic neurotoxicant exposure. Resistance of TIDA neurons to MPTP toxicity was correlated with a transient increase in UCHL-1 and a sustained elevation in parkin in the arcuate nucleus. TIDA neurons represent a DA neuron population with a unique and inherent ability to adapt to acute and chronic toxicant administration with a sustained elevation of the neuroprotective protein parkin. The correlation between the ability to increase parkin and UCHL-1 expression and the resistance of DA neurons to neurotoxicant exposure is consistent with a functional link between these features and an underlying differential susceptibility to toxicant-associated neurodegeneration.
authors: Neuroscience Program, Michigan State University, East Lansing, MI 48824, USA. benskeym@msu.edu
authors: Matthew
authors: M
authors: Benskey
authors: Ki Yong
authors: KY
authors: Lee
authors: Kevin
authors: K
authors: Parikh
authors: Keith J
authors: KJ
authors: Lookingland
authors: John L
authors: JL
authors: Goudreau
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology; D007031:Hypothalamus / Q000378:metabolism*; D020267:MPTP Poisoning / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008636:Mesencephalon / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D014446:Tyrosine 3-Monooxygenase; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D043222:Ubiquitin Thiolesterase; C496976:Uchl1 protein, mouse; D004298:Dopamine
references: J Neuropathol Exp Neurol. 2011 Aug;70(8):686-97
references: 21760537
references: Biochem Biophys Res Commun. 1990 Aug 16;170(3):1049-55
references: 2167668
references: Brain Res. 1979 Aug 10;171(3):545-51
references: 476488
references: Neurosci Lett. 1986 Dec 12;72(2):215-20
references: 2880321
references: J Neural Transm (Vienna). 2008 Jun;115(6):831-42
references: 18235988
references: Arch Biochem Biophys. 1993 Sep;305(2):271-7
references: 8373164
references: Free Radic Biol Med. 1998 Jan 1;24(1):76-84
references: 9436616
references: Brain Res. 1990 Oct 1;528(2):181-8
references: 2271921
references: Neurodegeneration. 1995 Sep;4(3):257-69
references: 8581558
references: J Biol Chem. 1993 Aug 5;268(22):16504-12
references: 8393868
references: J Microsc. 1987 Sep;147(Pt 3):229-63
references: 3430576
references: Hum Mol Genet. 2003 Nov 15;12(22):2957-65
references: 14519684
references: Ann N Y Acad Sci. 2003 Jun;991:1-14
references: 12846969
references: Hum Mol Genet. 2005 Dec 15;14(24):3885-97
references: 16278233
references: J Neurol. 2000 Apr;247 Suppl 2:II3-10
references: 10991663
references: Brain Res. 1997 Feb 21;749(1):44-52
references: 9070626
references: Brain Res. 1973 Sep 14;59:449-50
references: 4747772
references: Antioxid Redox Signal. 2005 May-Jun;7(5-6):685-93
references: 15890013
references: Methods Mol Biol. 1994;32:5-8
references: 7951748
references: J Neurochem. 2003 Sep;86(5):1297-307
references: 12911637
references: Handb Clin Neurol. 2007;83:329-42
references: 18808920
references: Environ Res. 2001 Jun;86(2):122-7
references: 11437458
references: Science. 2004 May 28;304(5675):1328-31
references: 15105460
references: Mol Ther. 2006 Nov;14(5):716-23
references: 16914382
references: Neurol Sci. 2008 Oct;29(5):293-301
references: 18941931
references: Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1638-43
references: 18230723
references: Neurotoxicology. 2012 Jun;33(3):321-31
references: 22342763
references: J Neurochem. 2005 Apr;93(2):422-31
references: 15816865
references: Parkinsonism Relat Disord. 2008;14 Suppl 2:S112-5
references: 18585085
references: Neurobiol Aging. 2003 Mar-Apr;24(2):197-211
references: 12498954
references: Hum Mol Genet. 2005 Sep 1;14(17):2571-86
references: 16049031
references: Ann Neurol. 2003;53 Suppl 3:S26-36; discussion S36-8
references: 12666096
references: Endocrinology. 2000 Jan;141(1):366-74
references: 10614659
references: Proc Natl Acad Sci U S A. 2005 Mar 1;102(9):3413-8
references: 15716361
references: Neurosci Lett. 2001 Jan 19;297(3):191-4
references: 11137760
references: Hum Gene Ther. 2005 Feb;16(2):262-70
references: 15761265
references: Brain Res. 1987 Feb 3;402(2):269-74
references: 3493826
references: Brain Res. 1990 Sep 10;527(1):21-31
references: 1980839
references: J Cell Biol. 2008 Dec 1;183(5):795-803
references: 19029340
references: Exp Neurol. 2007 Oct;207(2):289-301
references: 17678648
references: J Neurochem. 1990 Apr;54(4):1295-301
references: 2313288
references: J Biol Chem. 2000 Dec 8;275(49):38581-8
references: 10969076
references: Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10810-4
references: 15252205
references: Biochem Soc Symp. 1999;66:85-97
references: 10989660
references: Neuroscience. 2007 Jul 13;147(3):592-8
references: 17583437
references: Ann Neurol. 1978 Feb;3(2):129-33
references: 350130
references: Neuron. 2002 Dec 19;36(6):1007-19
references: 12495618
references: J Neurochem. 1988 Apr;50(4):1053-6
references: 2894407
references: Apoptosis. 2006 Jun;11(6):1049-59
references: 16544100
references: J Bioenerg Biomembr. 2004 Aug;36(4):375-9
references: 15377875
references: Mov Disord. 2005 Mar;20(3):271-82
references: 15580550
references: J Neurochem. 1988 Jun;50(6):1934-44
references: 2897430
references: Hum Mol Genet. 2004 Aug 15;13(16):1745-54
references: 15198987
references: Neuron. 2003 Sep 11;39(6):889-909
references: 12971891
references: Neurosci Lett. 1995 Aug 4;195(2):113-6
references: 7478263
references: J Neurochem. 1991 Jul;57(1):348-51
references: 2051170
references: Biochem Biophys Res Commun. 1986 May 29;137(1):310-5
references: 3487319
references: Trends Neurosci. 2007 May;30(5):244-50
references: 17418429
references: Neuroscience. 2001;106(3):589-601
references: 11591459
references: Synapse. 1996 Feb;22(2):93-9
references: 8787132
references: Neuroscience. 1997 Apr;77(4):1037-48
references: 9130785
references: Nat Neurosci. 2000 Dec;3(12):1301-6
references: 11100151