Aggregation of alpha-synuclein by DOPAL, the monoamine oxidase metabolite of dopamine.
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.
Burke
William J
WJ
Department of Neurology, Saint Louis VAMC and Saint Louis University Health Sciences Center, St Louis, MO 63125, USA.
Kumar
Vijaya B
VB
Pandey
Neeraj
N
Panneton
W Michael
WM
Gan
Qi
Q
Franko
Mark W
MW
O'Dell
Mark
M
Li
Shu Wen
SW
Pan
Yi
Y
Chung
Hyung D
HD
Galvin
James E
JE
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism*; D007150:Immunohistochemistry; D016631:Lewy Bodies / Q000378:metabolism* / Q000473:pathology; D018613:Microscopy, Confocal; D008995:Monoamine Oxidase / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D051844:alpha-Synuclein / Q000378:metabolism*
D051844:alpha-Synuclein; D015102:3,4-Dihydroxyphenylacetic Acid; D008995:Monoamine Oxidase; D004298:Dopamine