Aggregation of α-synuclein by DOPAL, the monoamine oxidase metabolite of dopamine

被引:185
作者
Burke, William J. [2 ,3 ,4 ]
Kumar, Vijaya B. [1 ,3 ,4 ,5 ]
Pandey, Neeraj [6 ]
Panneton, W. Michael [7 ,8 ]
Gan, Qi [7 ,8 ]
Franko, Mark W. [3 ,4 ]
O'Dell, Mark [6 ]
Li, Shu Wen [2 ,3 ]
Pan, Yi [2 ,3 ]
Chung, Hyung D. [9 ,10 ]
Galvin, James E. [6 ]
机构
[1] Jefferson Barracks VAMC, St Louis, MO 63125 USA
[2] St Louis VAMC, Dept Neurol, St Louis, MO 63125 USA
[3] St Louis Univ, Hlth Sci Ctr, St Louis, MO 63125 USA
[4] St Louis VAMC, Dept Med, St Louis, MO 63125 USA
[5] Vet Adm Med Ctr, Div Geriatr Res, St Louis, MO 63125 USA
[6] Washington Univ, Sch Med, Alzheimers Dis Res Ctr, Dept Neurol Anat & Neurobiol, St Louis, MO 63110 USA
[7] St Louis VAMC, Dept Pharmacol & Physiol Sci, St Louis, MO 63125 USA
[8] St Louis Univ, Hlth Sci Ctr, St Louis, MO 63125 USA
[9] St Louis VAMC, Dept Pathol, St Louis, MO 63125 USA
[10] St Louis Univ, Hlth Sci Ctr, St Louis, MO 63125 USA
关键词
Parkinson's disease; alpha-synuclein; 3,4-dihydroxyphenylacetaldehyde; dopamine metabolite;
D O I
10.1007/s00401-007-0303-9
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Parkinson's disease (PD) is a neurodegenerative disease characterized by the selective loss of dopamine (DA) neurons and the presence of alpha-synuclein (AS) aggregates as Lewy bodies (LBs) in the remaining substantia nigra (SN) neurons. A continuing puzzle in studying PD pathogenesis is that although AS is expressed throughout the brain, LBs and selective dopaminergic cell loss lead to characteristic clinical signs of PD, suggesting that there is a link between AS aggregation and DA metabolism. One potential candidate for this link is the monoamine oxidase (MAO) metabolite of DA, 3,4-dihydroxyphenylacetaldehyde (DOPAL), as neither DA nor DA metabolites other than DOPAL are toxic to SN neurons at physiological concentrations. We tested DOPAL-induced AS aggregation in a cell-free system, in vitro in DA neuron cultures and in vivo with stereotactic injections into the SN of Sprague-Dawley rats by Western blots, fluorescent confocal microscopy and immunohistochemistry. We demonstrate that DOPAL in physiologically relevant concentrations, triggers AS aggregation in the cell-free system, and in cell cultures resulting in the formation of potentially toxic AS oligomers and aggregates. Furthermore, DOPAL injection into the SN of Sprague-Dawley rats resulted in DA neuron loss and the accumulation of high molecular weight oligomers of AS detected by Western blot. Our findings support the hypothesis that DA metabolism via DOPAL can cause both DA neuron loss and AS aggregation observed in PD.
引用
收藏
页码:193 / 203
页数:11
相关论文
共 48 条
[1]   Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death [J].
Arrasate, M ;
Mitra, S ;
Schweitzer, ES ;
Segal, MR ;
Finkbeiner, S .
NATURE, 2004, 431 (7010) :805-810
[2]   Chronic systemic pesticide exposure reproduces features of Parkinson's disease [J].
Betarbet, R ;
Sherer, TB ;
MacKenzie, G ;
Garcia-Osuna, M ;
Panov, AV ;
Greenamyre, JT .
NATURE NEUROSCIENCE, 2000, 3 (12) :1301-1306
[3]  
BLASCHKO H, 1952, PHARMACOL REV, V4, P415
[4]   3,4-Dihydroxyphenylacetaldehyde: A Potential Target for Neuroprotective Therapy in Parkinson's Disease [J].
Burke, W. J. .
CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS, 2003, 2 (02) :143-148
[5]   Neurotoxicity of MAO metabolites of catecholamine neurotransmitters: Role in neurodegenerative diseases [J].
Burke, WJ ;
Li, SW ;
Chung, HD ;
Ruggiero, DA ;
Kristal, BS ;
Johnson, EM ;
Lampe, P ;
Kumar, VB ;
Franko, M ;
Williams, EA ;
Zahm, DS .
NEUROTOXICOLOGY, 2004, 25 (1-2) :101-115
[6]   3,4-dihydroxyphenylacetaldehyde is the toxic dopamine metabolite in vivo: implications for Parkinson's disease pathogenesis [J].
Burke, WJ ;
Li, SW ;
Williams, EA ;
Nonneman, R ;
Zahm, DS .
BRAIN RESEARCH, 2003, 989 (02) :205-213
[7]   Catecholamine monoamine oxidase a metabolite in adrenergic neurons is cytotoxic in vivo [J].
Burke, WJ ;
Li, SW ;
Zahm, DS ;
Macarthur, H ;
Kolo, LL ;
Westfall, TC ;
Anwar, M ;
Glickstein, SB ;
Ruggiero, DA .
BRAIN RESEARCH, 2001, 891 (1-2) :218-227
[8]   Norepinephrine transmitter metabolite is a selective cell death messenger in differentiated rat pheochromocytoma cells [J].
Burke, WJ ;
Schmitt, CA ;
Gillespie, KN ;
Li, SW .
BRAIN RESEARCH, 1996, 722 (1-2) :232-235
[9]   Dopamine promotes α-synuclein aggregation into SDS-resistant soluble oligomers via a distinct folding pathway [J].
Cappai, R ;
Leck, SL ;
Tew, DJ ;
Williamson, NA ;
Smith, DP ;
Galatis, D ;
Sharples, RA ;
Curtain, CC ;
Ali, FE ;
Cherny, RA ;
Culvenor, JG ;
Bottomley, SP ;
Masters, CL ;
Barnham, KJ ;
Hill, AF .
FASEB JOURNAL, 2005, 19 (08) :1377-+
[10]   A focus on the synapse for neuroprotection in Alzheimer disease and other dementias [J].
Coleman, P ;
Federoff, H ;
Kurlan, R .
NEUROLOGY, 2004, 63 (07) :1155-1162